Nirogacestat

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Nirogacestat
Nirogacestat.svg
Clinical data
Trade names Ogsiveo
Other namesPF-03084014, PF-3084014
AHFS/Drugs.com Ogsiveo
MedlinePlus a624011
License data
Routes of
administration 		By mouth
Drug class Gamma-secretase inhibitor
ATC code
Legal status
Legal status
Identifiers
  • (S)-2-((S)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
CAS Number
PubChem CID
PubChemSID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C27H41F2N5O
Molar mass 489,64 g/mol
3D model (JSmol)
Solubility in water 11.4 mg/mL (water
  • CCC[C@@](N[C@@]1([H])CCC2=CC(F)=CC(F)=C2C1)([H])/C(O)=N/C3=CN(C(C)(CNCC(C)(C)C)C)C=N3
  • InChI=1S/C27H41F2N5O/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35)/t20-,23-/m0/s1
  • Key:VFCRKLWBYMDAED-REWPJTCUSA-N

Nirogacestat, sold under the brand name Ogsiveo, is an anti-cancer medication used for the treatment of desmoid tumors. [1] [2] [3] It is a selective gamma secretase inhibitor [4] that is taken by mouth. [1]

Contents

Nirogacestat was approved for medical use in the United States in November 2023. [2] It is the first medication approved by the US Food and Drug Administration (FDA) for the treatment of desmoid tumors. [2] [5] The FDA considers it to be a first-in-class medication. [6] European Medicines Agency (EMA) considers it an orphan drug. [7] and issued a positive opinion on its approval [8]

Medical uses

Nirogacestat is indicated for adults with progressing desmoid tumors who require systemic treatment. [1] [2]

Adverse effects

Nirogacestat treatment has been associated with several notable adverse effects across multiple studies. Hypophosphatemia is a significant and common side effect, with an incidence exceeding 40% in patients with various cancers including desmoid tumors, sarcoma, metastatic breast cancer, and solid organ cancers. [9] Gastrointestinal toxicity is another concern, and glucocorticosteroid pretreatment and post-treatment regimens have shown efficacy in mitigating these effects in clinical trials. [10]

Reproductive toxicity has been observed in animal studies, with findings including ovarian atrophy, amenorrhea, premature menopause, reduced testes weight, and decreased sperm concentration and motility; some of these effects may be irreversible. There is a possible risk of non-melanoma skin cancer development. In vivo rat studies showed embryotoxicity, including decreased body weight, implantation loss and subcutis edema at doses lower than the recommended human dose. [11] [12] Additionally, there has been a reported case of eruptive milia in association with nirogacestat therapy. [13]

Nirogacestat have been found to induce grade 1 or 2 adverse effects, with exception of hypophosphatemia at grade 3: [14] [2] [3]

Pharmacology

Pharmacodynamics

Nirogacestat works as a gamma secretase inhibitor, which blocks the activation of the Notch receptor, stopping tumor growth. [11]

Nirogacestat's indirect action on Notch intracellular domain (NICD) and amyloid precursor protein (APP) due to gamma-secretase inhibition are described in the table below.

Nirogacestat IC50 values
TargetIC50 (nM)
gamma-secretase (cell-free assay)6.2 [15] ; 1.2 [16]
NICD [17] Notch1 30.6
Notch2 27.8
Notch3 11.5
Notch4 42.6
APP [17] intracellular domain19.3
amyloid β-4025.8

Nirogacestat's binding to gamma-secretase assessed with cryogenic electron microscopy showed that it localises in the persenilin 1 catalytic subunit. Four hydrogen bonds are involved in this interaction, where two come from lysine (position 380 within the amino-acid sequence of gamma-secretase) and two from leucine (position 432). Its aligment selectively obstructs the site of Notch cleavage by gamma-secretase, which occurs in its β-sheet, allowing inhibition of downstream Notch signalling. [17]

Nirogacestat trifluoropropyl derivative with enhanced persenilin binding pocket affinity Nirogacestat trifluoropropyl derivative.png
Nirogacestat trifluoropropyl derivative with enhanced persenilin binding pocket affinity

Moreover, nirogacestat's pharmacophore is consistent with other gamma-secretase inhibitors (e.g., crenigacestat) in terms of three dimensional arrangement in the binding cavity. Leucine342 hydrogen bond interaction is shared amongst these compounds [17]

A slight modification of nirogacestat's structure, where the propyl group is substituted by a trifluoropropyl group, results in enhanced binding-pocket occupation and better inhibition. [17]

Pharmacokinetics

Nirogacestat's pharmacokinetic parameters in patients with desmoid tumors are as follows: [11]

Pharmacokinetic profile of nirogacestat
Steady state
Time to steady-state approx. 6 days
Cmax 580 ng/mL
AUC 0-τ3370 ng·h/mL
AUC∞ [22] at 50 mg dose375-725 ng·h/mL
at 100 mg dose1200-233 ng·h/mL
at 150 mg dose2000-4000 ng·h/mL
Accumulation ratio1.6 (median 1.3-4.6)
Absorption
Time to peak concentration (Tmax)1.5 h (median 0.5-6.5)
Absolute bioavailability 19%
Food effect [dose-normalised geometric mean ratio, 90% CI)Cmax93% (55%, 166%)
AUC114% (76%, 171%)
Effective permeability (in vivo, human Caco-2 cells)2.7 [23]
Distribution
Protein bindingSerum protein99.6%
Human albumin 94.6%
α1-acid glycoprotein 97.9%
Plasma unbound fraction (in mice)2.6% [23]
Microsomal unbound fraction (human liver cells)81% [23]
Blood-plasma concentration ratio (in mice)0.52 [23]
Apparent volume of distribution (observed/predicted)1430 L (mean 65)
Metabolism
PrimaryN-dealkylation via CYP3A4 (85%)
SecondaryCYP3A4, CYP2C19, CYP2C9, CYP2D6
Elimination
Intrinsic clearance (in mice)227 mL/min·kg
Apparent systemic clearance (observed/predicted)45 L/hr (mean 58)
Terminal elimination half-life (t1/2)23 h (mean 37)
Excretion Feces38%
Urine17% (<1% unchanged)
Expired air9.7%

Drug interactions

Nirogacestat can interfere with several drugs that are metabolised through cytochrome P450 pathways, especially through CYP3A family and CYP2C19. Additionally, gastric acid-neutralising medications impired its absorption and thus reduced its plasma concentration. [11]

Chemistry

Physicochemical properties

Nirogacestat's chemical properties were evaluated in silico and in vitro in mice and are as follows:

Nirogacestat's chemical profile
Parameterin silicoin vitro
lipophilicity (cLogP) [23] 4.012.07
solubility in water (mg/mL) [23] 0.32 (pH=9.7)2.2 (pH=5.3); 11.4 (pH=4.4) [11]
pKa [23] 6.4, 8.95.8, 7.1
octanol-water partition coefficient (XlogP) [24] 4.8–
topological polar surface area (TPSA) [24] 71 Ų–

Synthesis

Nirogacestat can be synthesised through the following pathway:

Nirogacestat synthesis Nirogacestat synthesis.png
Nirogacestat synthesis

2-(2,4-difluorophenyl)acetyl chloride (1) undergoes cyclisation reaction with ethene to yield 2. Then, 2 reacts with tert-butyl (2S)-2-aminopentanoate, yielding 3 that is further hydrolysed to remove the tert-butyl group, yielding 4. To finally obtain nirogacestat, 4 is reacted with 5 ([1-[2-(2,2-dimethylpropylamino)-1,1-dimethyl-ethyl]imidazol-4-yl]azinate). [16]

Alternatively, 6 reacts with 7, where the trifluoromethylsulfonate moiety acts as a leaving group and the tert-butyl moiety acts as a protecting group, to avoid the reaction of carboxyl group with amine group in 6. This reaction is performed in iso-propanol and an inorganic acid (such as hydrobromic or hydrochloric acid). Obtained 8 undergoes cyclisation reaction using 9 (1,1'-carbonyldiimidazole) in a polar aprotic solvent, yielding 10. Then, reaction with 11 creates nirogacestat. [25]

Alternative nirogacestat synthesis Nirogacestat synthesis 2.png
Alternative nirogacestat synthesis

The trifluoromethylsulfonyl group in 7 can be replaced with tert-butyloxycarbonyl group (Boc). Reaction of 10 with 11 is conducted a condensing agent, precisely O-(1,2-dihydro-2-oxo-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) in N,N-diisopropylethylamine. [26]

Formation of several side products should be addressed. The above synthetic pathway allows to minimise side product creation to less than 1%. [25] An important example is adverse cyclisation of the product of reaction of 10 with 11 shown below (compound 12). To avoid this situation, to the mixture of 10 and 11, compound 6 and hydrobromic acid is added. [25]

Side product - compound 12 Nirogacestat synthesis side product.png
Side product – compound 12

Compounds 5 and 11 can be synthesised as follows [27] :

Compound 5 and 11 synthesis Nirogacestat intermediates synthesis.png
Compound 5 and 11 synthesis

A undergoes reduction using diisobutylaluminium hydride (DIBAL-H) in dichloromethane (DCM), obtaining B. Then B is condensed with 2,2-dimethylpropan-1-amine with Na(OAc)3BH in DCM on a molecular sieve, yielding 5. To synthesise 11, 5 undergoes reduction with hydrogen on Pd/C in methanol.

Compound 6 and tert-butyl (2S)-2-aminopentanoate may be synthesised using an enzyme-driven process, using respectively: ATA ω-transaminase with isopropylamine, pyridoxal phosphate, phosphoric acid and potassium hydroxide; alcohol dehydrogenase, glucose dehydrogenase, glucose monohydrate, NAD+ in phosphate buffer and glycerol. [29] This enzymatic process is used to obtain 6 from 2 while minimising stereoisomer side products (the reaction is selective towards the S isomer). [30]

Crystalline forms

Nirogacestat can exist in several crystalline forms, where the form used clinically is an anhydrous dihydrobromide salt that has a primitive monoclinic Bravais lattice (form A). It exhibits high polymorphic purity of at least 80%. In water, it crystallises as small needles and does not change its lattice, suggesting stability. Other forms can change into form A in methanol, suggesting instability. However, form A in methanol mixed with other reagents (acetone, trichloromethane, methyl-tert-butyl ether and N-Methyl-2-pyrrolidone) changes its lattice. In clinical settings, this transformation is not observed. [31]

Form A characteristics [31]
Powder X-ray diffraction pattern2θ = 8.8°, 9.8°, 23.3°
Melting point254 °C
Unit cella = 10.035 Å, b= 7.532 Å, c = 20.092 Å
volume = 1518.1 Å
Particle sizevolumetric median diameter0.5-15 μm
volumetric diameter of 90% of particles2-30 μm
volume-weighted mean diameter5-200 μm

History

N-pyrrolidine pre-clinical compound leading to nirogacestat's discovery Pre-clinical compound leading to discovery of nirogacestat.png
N-pyrrolidine pre-clinical compound leading to nirogacestat's discovery

Preclinical studies assessed different functional group configurations of a compound with a common backbone. Initially, N-pyrrolidine was selected for in vivo assay, which demonstrated significant inhibitory activity at gamma-secretase. Further studies aimed to optimise EC50-plasma concentration coefficient, which led to selection of nirogacestat for further studies. [16]

The effectiveness of nirogacestat was evaluated in DeFi (NCT03785964 [32] ), an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial in 142 adult participants with progressing desmoid tumors not amenable to surgery. [3] Participants were randomized to receive 150 milligrams (mg) of nirogacestat or placebo orally, twice daily, until disease progression or unacceptable toxicity. [2] The main efficacy outcome measure was progression-free survival (the length of time after the start of treatment for which a person is alive and their cancer does not grow or spread). [2] Objective response rate (a measure of tumor shrinkage) was an additional efficacy outcome measure. [2] The pivotal clinical trial demonstrated that nirogacestat provided clinically meaningful and statistically significant improvement in progression-free survival compared to placebo. [2] Additionally, the objective response rate was also statistically different between the two arms with a response rate of 41% in the nirogacestat arm and 8% in the placebo arm. [2] The progression-free survival results were also supported by an assessment of patient-reported pain favoring the nirogacestat arm. [2]

As of 2021, nirogacestat was in phase II clinical trials for unresectable desmoid tumors. [33] [ needs update ] In addition, a phase III clinical trial, DeFi, was in progress for nirogacestat for adults with desmoid tumors and aggressive fibromatosis. [34]

The FDA granted the application for nirogacestat priority review, fast track, breakthrough therapy, and orphan drug designations. [2] [3] The FDA granted the approval of Ogsiveo to SpringWorks Therapeutics Inc. [2]

Society and culture

Nirogacestat was granted breakthrough therapy designation by the FDA in September 2019, for adults with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. [35]

In June 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ogsiveo, intended for the treatment of adults with progressing desmoid tumors. [36] The applicant for this medicinal product is SpringWorks Therapeutics Ireland Limited. [36]

Research

Neurological disorders

Since gamma-secretase inhibitors are involved in producing amyloid β-peptide from amyloid precursor protein (APP), they may have application in the treatment of Alzheimer's disease. [37] Nirogacestat tested in guiena pig brain showed amyloid β-lowering activity with ED50 for amyloid β in guiena pig brain at 1.83 mg/kg, sc. [38] Another study showed, that IC50 values for cell-free enzyme assay (amyloid β1-40), whole-cell assay (amyloid β1-x) and CD25+ B- and T- cells in fetal thymic organ culture are respectively 6.2 nM, 1.2 nm and 1.3 nM. [39]

However, human phase 2 clinical tria of nirogacestatl showed no benefit in altering APP processing by nirogacestat. [40]

Nirogacestat may be useful for treating several other neurological diseases, including hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, inclusion body myositis, multiple sclerosis, mild cognitive impairment and Down's syndrome. [41]

Hematological malignancies

Multiple myeloma

Five clinical trials evaluated efficacy of nirogacestat with other anticancer therapies in multiple myeloma:

  • UNIVERSAL – nirogacestat and allogeneic CAR-T therapy ALLO-715. [42]
  • MajesTEC-2 – nirogacestat an teclistamab [43]
  • DREAMM 5 – nirogacestat in combination with belantamab mafodotin and pomalidomide [44] Results showed moderate response rate and allowed reduction of belantamab dose. One important advese effect associated with this treatment regimen were ocular evenets, including keratopathy, decreased corrected visual acuity. [45] DREAMM-5 clinical trial confirmed these findings. [46] [47]
  • MagnetisMM-4 – nirogacestat and elranatamab
  • PBCAR269A – nirogacestat and allogenic anit- BCMA CAR-T cell therapy, fludarabine and cyclophosphamide (terminated due to insufficient therapeutic effect.) [48]

Additionally, an in vitro and in vivo (plasma cells in healthy patients) study showed that nirogacestat rapidly increases membrane-bound BCMA receptor and decreases soluble BCMA concentrations, which in turn supports its potential to treat multiple myeloma. [49] However, this effect was only temporary, suggesting that a steady sate is required to maintain its efficacy. [50] Moreover, release of soluble BCMA into tear fluid is associated with keratopathy. [51]

Lymphoblastic leukemia and T-cell lymphoblastic lymphoma

A clinical trial testing nirogacestat's usefulness in treating lymphoblastic malignancies was conducted and its results showed that it inhibited HES4 gene expression in peripheral blood of treated patients. Since this transcription factor is involbed in Notch1-mediated T-cell development, this finding justifies further clinical trials to test its efficacy in blood cancers. [52] In vitro studies in Notch1-mutated acute lymphoblastic leukemia cell lines [53] confirmed HES4-inhibition and also presented evidence for decereasing expression of cMyc regulator. [15] Moreover, nirogacestat induced apoptosis markers, that is the active form of caspase-3 and cleaved (inactivated) PARP expression in human acute lymphoblastic leukemia cells. [54]

DSPE-PEG(2000)-DT7 DSPE-PEG(2000)-DT7.png
DSPE-PEG(2000)-DT7

One study tested a novel formulation of nirogacestat and dexamethasone, which were developed to be bound to a modified lecithin nanoparticles, targeting lymphoma cells. In vitro, this allowed to enhance dexamethasone-mediated cell death, through simultaneous glucocorticoid receptor hyperexpression and BCL2 inhibition. It also allowed to increase bone marrow accumulation. The peptide was synthesised from phopsphatidyletholamine bound to stearic acid chains and a pegyl group, an octapeptide (N-His-Arg-Pro-Tyr-Ile-Ala-His-Cys-C) and soy lecithin. [56]

Chronic lymphoblastic leukemia

HG3 cell line represents a testing environment for drugs that affect the progression of chronic lymphoblastic leukemia. Nirogacestat is capable of decrease the viability of these cells (using ATP quantification assay) compared to DMSO in both NOTCH1 wild-type and mutated cells (using CRISPR/Cas9 technology), suggesting a probable treatment regimen for this disease. When combined with a USP28 (ubiquitin specific peptidase 28) allosteric inhibition, this regimen was enhanced compared to nirogacestat alone. Both of these findings were statistically significant. [57]

Moreover, nirogacestat showed dose-dependent S and G2-M mitotic phase inhibition in Notch1-mutated CLL cells, lowering cell viability. [58]

Diffuse large B-cell lymphoma

Mutations in NOTCH2 genes in diffuse large-B cell lymphoma (DLBCL) can cause a relatively common resistance to R-CHOP treatment regimen. Nirogacestat promotes ubiquitin-dependent Notch2 degradation via E3 ligases (KLHL6 and FBXW7), stopping mRNA expression of MYC and KRAS genes, which are involved in downstream signalling leading to cell proliferation. Moreover, combination with an AKT inhibitor ipatasertib further enhanced apoptotic promotion in malignant R-CHOP-resistant lymphocytes B. However, the inhibitory constant (IC50) of nirogacestat in dual KLHL6 and FBXW7 human DLBCL-xenotransplanted mutant mice (with a deletion in degron sites in E3 ligases, that recognise Notch2) was over two-times higher, than in the wild type. [59]

Acute myeloid leukemia

Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three in vitro models, each representing a different subtype of acute myeloid leukemia (HL60 – AML M2 with TP53 deletion and CDKN2A C238T [60] , Kasumi-1 – AML M2 with AML1-ETO fusion gene [61] and OCI-AML3 – AML M4 with NPM1 and DNMT3A R882c mutations [62] ) as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of cytarabine than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found. [63]

Reverse transcriptase PCR assay found that nirogacestat in combination with dexamethasone significantly influenced expression of Notch-related genes (increased: DTX1 – an ubiquitin ligase, decreasing T-cell development in thymus, peripherial blood and spleen [64] , BCL2L11 – a protein involved in Bcl-2-related apoptosis ;decreased: HES1 – a transcription factor repressing NR3C1 [65] glucocorticoid receptor upregulation [66] ). This finding shows that nirogacestat poses an ability to reverse glucocorticoid resistance in AML, thereby significantly decreasing tumor mass. Moreover, glucocorticoid administration attenuated nirogacestat-induced gastrointestinal toxicity, by stopping goblet cell metaplasia related to Notch1 suppression, and increasing Math1 gene. Nirogacestat also decreases β-actin expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with rapamycin's antileukemic properties. [67] [68]

Splenic marginal zone lymphoma

In vitro studies showed that concomitant nirogacestat administration with decitabine, ibrutinib, idelalisib, and an investigational drug 3-dezaneplanocin A intensively increased cell deth in splenic marginal zone malignant lymphocytes. [69]

Solid tumors

Colorectal cancer

In mouse with colorectal cancer harboring mutated adenomatous polyposis coli gene (APC), that exhibit enhanced Notch signalling, nirogacestat decreased cell migration, invasion and growth. [70]

Pancreatic adenocarcinoma

One study tested nirogacestat alone and with gemcitabine in pancreatic ductal adenocarcinoma patient-derived xenografts in mice and showed that both treatment arms showed regression of cell division and decreased angiogenesis. [71]

Phase 2 clinical trial of nirogacestat in metastatic pancreatic cancer was terminated due to changes in Pfizer's strategy in drug development. [72]

Venous thromboembolism is a serious complication of panceratic cancer that is mediated by interleukin-6 (IL-6), thyroid peroxidase (TPO) and tissue factor (TF) secretion from tumor-associated stromal cells. Nirogacestat, in an in vivo study with mice injected with pancreatic adenocarcinoma cells, showed a steep decrease in these markers. This hyperexpression is also present in human plasma in patients with this malignancy. This effect was shown to be mediated by Jagged-Notch interaction. [73]

Lung adenocarcinoma

Nirogacestat was shown to reverse resistance to tyrosine kinase inhibitors such as gefitinib in EGFR-mutated lung adenocarcinoma, precisely the form where there exists a EGFRT790M/L858R mutation. [74]

Breast cancer

Nirogacestat emerged as a possible adjunctive treatment to taxane treatment of triple-negative breast cancer. Notch receptor intracytoplasmic domain being internalised into a singnal-receiving cell, induces a signal transduction pathway associated with pregnane X receptor that causes BCRP, P-glycoprotein and CYP3A4 activation, causing drug resistance. [75] It has a slight preference towards persenilin 2 versus 1 catalytic subunits of gamma-secretase. [76]

Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three in vitro models, each representing a different subtype of acute myeloid leukemia (HL60 – AML M2 with TP53 deletion and CDKN2A C238T [77] , Kasumi-1 – AML M2 with AML1-ETO fusion gene [78] and OCI-AML3 – AML M4 with NPM1 and DNMT3A R882c mutations [79] ) as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of cytarabine than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found. [80]

Reverse transcriptase PCR assay found that nirogacestat in combination with dexamethasone significantly influenced expression of Notch-related genes (increased: DTX1 – an ubiquitin ligase, decreasing T-cell development in thymus, peripherial blood and spleen [81] , BCL2L11 – a protein involved in Bcl-2-related apoptosis ;decreased: HES1 – a transcription factor repressing NR3C1 [82] glucocorticoid receptor upregulation [83] ). This finding shows that nirogacestat poses an ability to reverse glucocorticoid resistance in AML, thereby significantly decreasing tumor mass. Moreover, glucocorticoid administration attenuated nirogacestat-induced gastrointestinal toxicity, by stopping goblet cell metaplasia related to Notch1 suppression, and increasing Math1 gene. Nirogacestat also decreases β-actin expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with rapamycin's antileukemic properties. [84] [85]

In human mitoxantrone-resistant breast carcinoma cell line [86] nirogacestat inhibits their migration, but shows no antiproliferative effects. [87]

In estrogen receptor-positive metastatic breast cancer, a phase 1 study showed that co-administration of nirogacestat with exemestane inhibited metastasis. [88]

Since angiogenesis associated with tumor development is regulater by YAP/TAZ cytoplasm translocation from nucleus, nirogacestat was tested as a possible inhibitor of cytoplasm transport of these transcription factors. In one study, it was shown that nirogacestat significantly reduced cytoplasmatic concentration of YAP and TAZ, suggesting antiangiogenic activity in breast cancer tumor environment. [89]

Nirogacestat's inhibitory effect on SMAD interaction with intracellular domain cleaved by g-secretase and FOXL2 expression Nirogacestat and ovarian granulosa cell proliferation.png
Nirogacestat's inhibitory effect on SMAD interaction with intracellular domain cleaved by γ-secretase and FOXL2 expression

Ovarian granulosa cell tumor

Similarly to abovementioned diseases, the mechanism of action of nirogacestat supported the launch of a phase 2 clinical trial. [90] Proposed influence of nirogacestat on these tumors is that overactivation of Notch causes FOXL2 hyperexpression, which is inhibited by this drug. It was confirmed by studying nirogacestat's effect on a cell line, in which a mutation in FOXL2C134W is present that causes enhanced gamma-secretase activity on SMAD-mediated signalling pathway. [91] However, nirogacestat's usefulness in this model is controvesial, since some studies show no clinical benefit. [92]

Prostate cancer

In vitro studies of nirogacestat in castration-resistant prostate cancer cells showed, that it reversed enzalutamide and docetaxel resistance and itself halted the further development of cancerous malignancy. [93] In PTEN-deficient cancer cells, nirogacestat induced tumor growth arrest by inducing cellular senescence. [94]

Hepatocellular carcinoma and squamous cell carcinoma

Nirogacestat has the ability of suppresing hepatocellular carcinoma growth and metastasis, by decreasing Stat3 and Akt signalling activity beside Notch1 inhibition. [95] Concomitant administration of sorafenib further decreased hepatocellular carcinoma spheroids (stem-like cells), where this effect is attributed to nirogacestat's ability to reduce Notch1-induced sorafenib resistance via decrasing epithelial-mesenchymal transition (EMT), where it is associated with attenuated expression of EMT-related genes (i.e., Snail1, N-cadherin, ABCG2, Nanog and Oct4), enhanced expression of E-cadherin and inhibition of survival signalling pathways (Mek/Erk and PI3K/Akt). It also reduced tumor angiogenesis in vivo. [96]

Similar mechanisms are responsible for nirogacestat/erlotinib combination's ability to reduce head and neck and oral squamous cell carcinoma cell invasion and tumor growth. [97] [98]

Melanoma

Notch signalling pathway increases MAPK pathway in uveal and cutaneous melanoma. Therefore, it can cause resistance to cobimetinib. In BRAFV600E metastatic melanoma, nirogacestat was shown to inhibit resistance to therapy, whereas in GNAQQ209L uveal melanoma it diminished cancer cell migration. Overall, it was also shown to inhibit c-jun and Erk1/2 activation. [99]

Cholangiocarcinoma

TAZ zinc finger containing transcription factors are involved in development of cholangiocarcinoma. Since its expression is increased indirectly by Notch pathway, nirogacestat may be a potential treatment for this disease. The mechanism explaining this potential application is that Notch induces METLL3 expression, that causes N-6-methyladenosine modification of TAZ mRNA, which causes its hyperexpression. [100]

Other diseases

Osteolytic diseases

In vivo studies showed nirogacestat's activity at receptor activator of nuclear factor-κB ligand (RANKL), which is implicated in osteoclastogenesis and lipopolysaccharide-induced bone resorption. It inhibited bone resorption and attenuated mRNA expression of osteoclast-specific markers (calcitonin receptor, tartarate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, V-ATPase d2, nuclear factor of activated T-cells cytoplasmic 1). [101]

Recessive dystrophic epidermolysis bullosa

Notch signalling pathway is involved in profibrotic activity, causing dystrophic epiderolysis bullosa. Nirogacestat can be a potential treatment for this disease, since it reduces fibroblast contractility and secretion of TGF-β1 and collagens. [102]

Polycystic kidney disease

In one study, nirogacestat was an agent tested among other compounds, including another Notch inhibitor – dibenzazepine. Both of them were shown to inhibit forskolin-mediated Notch3 expression in ADPKD (Autosomal Dominant Polycystic Kidney Disease) cells. [103]

Microvillus inclusion disease

Studies in mice pretreated with tamoxifen in order to create myosin Vb-deficient and -mutated intestinal epithelium cells showed that nirogacestat halted mislocalisation of enterocyte sodium transporters (e.g., sodium–hydrogen antiporter 3 and sodium/glucose cotransporter 1) only in deficient, but not mutated, mice tissues. Even though this study was not aimed at utilising nirogacestat as a potential treatment, it showed that total loss and malfunction of myosin Vb contribute to different subtypes of microvillus inclusion disease. [104]

Retinal degenerative diseases

Transplantation of retinal organoids derived from human embryonic stem cells and induced pluripotent stem cells in conjunction with nirogacestat administration in mice presenting with retinal degeneration increased both rod and cone generation in the retina. However, this process is highly inefficient, since most of the transplanted cells undergo apoptosis, outflow from the injection site, graft rejection and produce inflammatory response. [105]

Diabetes

Concomitant administration of nirogacestat and a FOXO1 inhibitor in streptozocin-induced diabetic mice was shown to increase enteroendocrine progenitor cells differentiation into β-cells, which secrete insulin, thereby decreasing plasma glucose concentration. This effect influenced hepatic glucose homeostasis, by increasing the expression of glucokinase (consequently inducing glycogen synthesis) , and suppressing gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression. [106]

Analogs

2,4-difluorophenyl derivatives (A375 - melanoma cell line, MDA-MB-231 - triple-negative breast cancer cell line, PCC-1 - prostate adenocarcinoma cell line, HF - human fibroblasts) 2,4-difluorophenyl derivatives.png
2,4-difluorophenyl derivatives (A375 – melanoma cell line, MDA-MB-231 – triple-negative breast cancer cell line, PCC-1 – prostate adenocarcinoma cell line, HF – human fibroblasts)

The 2,4-difluorophenyl moiety of nirogacestat exhibits strongly polarised carbon-fluorine bonds; therefore it can create hydrogen bonds with biological targets. This characteristic led to development of novel molecules that can be utilised in treatment of several cancers. Their structure is based on 1-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid, which is conjugated with other moieties. Smallest EC50 values were shown for following compounds. [107]

References

  1. 1 2 3 4 "Ogsiveo- nirogacestat tablet, film coated". DailyMed. 8 December 2023. Archived from the original on 12 December 2023. Retrieved 12 December 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA Approves First Therapy for Rare Type of Non-Cancerous Tumors". U.S. Food and Drug Administration (FDA) (Press release). 27 November 2023. Archived from the original on 28 November 2023. Retrieved 28 November 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  3. 1 2 3 4 "FDA approves nirogacestat for desmoid tumors". U.S. Food and Drug Administration (FDA). 27 November 2023. Archived from the original on 30 November 2023. Retrieved 30 November 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  4. ↑ Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, et al. (September 2019). "Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo". Experimental Cell Research. 382 (1) 111470: 111470. doi:10.1016/j.yexcr.2019.06.015. PMID   31211955. S2CID   195065514.
  5. ↑ "SpringWorks Therapeutics Announces FDA Approval of Ogsiveo (nirogacestat) as the First and Only Treatment for Adults with Desmoid Tumors" (Press release). SpringWorks Therapeutics. 27 November 2023. Archived from the original on 28 November 2023. Retrieved 28 November 2023– via GlobeNewswire.
  6. ↑ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
  7. ↑ "EU/3/19/2214 - orphan designation for treatment of soft tissue sarcoma | European Medicines Agency (EMA)". www.ema.europa.eu. 23 January 2020. Retrieved 22 July 2025.
  8. ↑ "Ogsiveo | European Medicines Agency (EMA)". www.ema.europa.eu. 20 June 2025. Retrieved 22 July 2025.
  9. ↑ Gudsoorkar P, Wanchoo R, Jhaveri KD (1 July 2023). "Nirogacestat and Hypophosphatemia". Kidney International Reports. 8 (7): 1478. doi: 10.1016/j.ekir.2023.04.023 . ISSN   2468-0249. PMC   10334393 . PMID   37441471.
  10. ↑ Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, et al. (1 June 2010). "Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design". Molecular Cancer Therapeutics. 9 (6): 1618–1628. doi:10.1158/1535-7163.MCT-10-0034. ISSN   1535-7163. PMID   20530712.
  11. 1 2 3 4 5 "HIGHLIGHTS OF PRESCRIBING INFORMATION – OGSIVEO (nirogacestat) tablets, for oral use" (PDF). Retrieved 21 July 2025.
  12. ↑ Loggers ET, Chugh R, Federman N, Hartner L, Riedel RF, Cho S, et al. (15 August 2024). "Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study" . Cancer. 130 (16): 2812–2821. doi: 10.1002/cncr.35324 . ISSN   0008-543X. PMID   38703010.
  13. ↑ Gutierrez Y, DeClerck B, Hsiao J, Lee KH (June 2025). "New Onset Hidradenitis Suppurativa and Eruptive Milia Associated with Gamma Secretase Inhibitor Therapy in a Patient with Desmoid Tumor: A Case Report". JAAD Case Reports. doi: 10.1016/j.jdcr.2025.05.042 .
  14. ↑ Chen AP, Hogu M (18 May 2023). "Phase II Trial of the γ-secretase Inhibitor Nirogacestat (PF-03084014) in Adults with Desmoid Tumors/Aggressive Fibromatosis" (PDF). ClinicalTrials.gov . p. 11. Retrieved 21 July 2025.
  15. 1 2 Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, et al. (1 June 2010). "Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design". Molecular Cancer Therapeutics. 9 (6): 1618–1628. doi:10.1158/1535-7163.MCT-10-0034. ISSN   1535-7163. PMID   20530712.
  16. 1 2 3 4 Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown TM, Coffman KJ, et al. (May 2011). "Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014". Bioorganic & Medicinal Chemistry Letters. 21 (9): 2637–2640. doi:10.1016/j.bmcl.2010.12.118. PMID   21269827.
  17. 1 2 3 4 5 Guo X, Li H, Lu X, Liu H, U K, Yan C, et al. (April 2025). "Structural basis of human γ-secretase inhibition by anticancer clinical compounds" . Nature Structural & Molecular Biology. 32 (4): 719–728. doi:10.1038/s41594-024-01439-8. ISSN   1545-9985. PMID   39653842.
  18. ↑ Bank RP. "RCSB PDB - 8KCT: Cryo-EM structure of human gamma-secretase in complex with Nirogacestat". www.rcsb.org. Retrieved 22 July 2025.
  19. ↑ Guo X, Li H, Lu X, Liu H, U K, Yan C, et al. (April 2025). "Structural basis of human γ-secretase inhibition by anticancer clinical compounds" . Nature Structural & Molecular Biology. 32 (4): 719–728. doi:10.1038/s41594-024-01439-8. ISSN   1545-9993. PMID   39653842.
  20. ↑ Bank RP. "RCSB PDB - 8KCT: Cryo-EM structure of human gamma-secretase in complex with Nirogacestat". www.rcsb.org. Retrieved 22 July 2025.
  21. ↑ Guo X, Li H, Lu X, Liu H, U K, Yan C, et al. (April 2025). "Structural basis of human γ-secretase inhibition by anticancer clinical compounds" . Nature Structural & Molecular Biology. 32 (4): 719–728. doi:10.1038/s41594-024-01439-8. ISSN   1545-9993. PMID   39653842.
  22. ↑ Lim A, Cheng S, Shearer TW, Williams R, Patterson K (16 January 2024) [19 May 2023]. "Treatments with nirogacestat – Patent US11,872,211 B2" (PDF). US Patent Office.
  23. 1 2 3 4 5 6 7 Hosea NA, Jones HM (1 April 2013). "Predicting Pharmacokinetic Profiles Using in Silico Derived Parameters" . Molecular Pharmaceutics. 10 (4): 1207–1215. doi:10.1021/mp300482w. ISSN   1543-8384. PMID   23427934.
  24. 1 2 "Nirogacestat". PubChem. Retrieved 23 July 2025.
  25. 1 2 3 4 Patterson K, Hatcher M (30 September 2022). "Synthesis of nirogacestat". US Patent Office. 1 (lines 35-67), 2 (lines 1-67), 3 (lines 1-67), 4 (lines (48-59), 22 (lines 28-50) – via Google Patents.
  26. ↑ Mei H, Han J, Klika KD, Izawa K, Sato T, Meanwell NA, et al. (January 2020). "Applications of fluorine-containing amino acids for drug design" . European Journal of Medicinal Chemistry. 186: 111826. doi:10.1016/j.ejmech.2019.111826. PMID   31740056.
  27. ↑ Wang YT, Yang PC, Zhang YF, Sun JF (February 2024). "Synthesis and clinical application of new drugs approved by FDA in 2023" . European Journal of Medicinal Chemistry. 265: 116124. doi:10.1016/j.ejmech.2024.116124. PMID   38183778.
  28. ↑ Wang YT, Yang PC, Zhang YF, Sun JF (February 2024). "Synthesis and clinical application of new drugs approved by FDA in 2023" . European Journal of Medicinal Chemistry. 265: 116124. doi:10.1016/j.ejmech.2024.116124. PMID   38183778.
  29. ↑ "Chemoenzymatic Route to Chiral Gamma Secretase Inhibitor Intermediates" . Synfacts. 13 (08): 0871. August 2017. doi:10.1055/s-0036-1590693. ISSN   1861-1958.
  30. ↑ Cui Y, Gao Y, Yang L (March 2024). "Transaminase catalyzed asymmetric synthesis of active pharmaceutical ingredients". Green Synthesis and Catalysis. doi: 10.1016/j.gresc.2024.03.003 .
  31. 1 2 "WIPO - Search International and National Patent Collections". patentscope.wipo.int. Retrieved 22 July 2025.
  32. ↑ SpringWorks Therapeutics, Inc. (17 January 2025). A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF) (Report). clinicaltrials.gov.
  33. ↑ Clinical trial number NCT04195399 for "A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014) in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors" at ClinicalTrials.gov
  34. ↑ Clinical trial number NCT03785964 for "A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Nirogacestat Versus Placebo in Adult Patients With Progressing Desmoid Tumors/Aggressive Fibromatosis (DT/AF)" at ClinicalTrials.gov
  35. ↑ "FDA Grants Nirogacestat Breakthrough Designation for Desmoid Tumors". OncLive. 4 September 2019. Archived from the original on 25 June 2021. Retrieved 25 June 2021.
  36. 1 2 "Ogsiveo EPAR". European Medicines Agency (EMA). 20 June 2025. Retrieved 26 June 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  37. ↑ Hur JY (April 2022). "γ-Secretase in Alzheimer's disease". Experimental & Molecular Medicine. 54 (4): 433–446. doi: 10.1038/s12276-022-00754-8 . ISSN   2092-6413. PMC   9076685 . PMID   35396575.
  38. ↑ Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown TM, Coffman KJ, et al. (1 May 2011). "Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014". Bioorganic & Medicinal Chemistry Letters. Recent Advances in Medicinal Chemistry. 21 (9): 2637–2640. doi:10.1016/j.bmcl.2010.12.118. ISSN   0960-894X. PMID   21269827.
  39. ↑ Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, et al. (July 2010). "Pharmacodynamics and Pharmacokinetics of the γ-Secretase Inhibitor PF-3084014" . The Journal of Pharmacology and Experimental Therapeutics. 334 (1): 269–277. doi:10.1124/jpet.110.167379. PMID   20363853 – via Elsevier Science Direct.
  40. ↑ Wischik CM, Harrington CR, Storey JM (April 2014). "Tau-aggregation inhibitor therapy for Alzheimer's disease". Biochemical Pharmacology. 88 (4): 529–539. doi: 10.1016/j.bcp.2013.12.008 . PMID   24361915.
  41. ↑ US 7795447B2,Brodney MA, Coffman KJ,"Imidazole compounds for the treatment of neurodegenerative disorders",issued 14 September 2010
  42. ↑ Clinical trial number NCT04093596 for "A Single-Arm, Open-Label, Phase 1 Study of the Safety, Efficacy, and Cellular Kinetics/Pharmacodynamics of ALLO-715 to Evaluate an Anti-BCMA Allogeneic CAR T Cell Therapy With or Without Nirogacestat in Subjects With Relapsed/Refractory Multiple Myeloma" at ClinicalTrials.gov
  43. ↑ Clinical trial number NCT04722146 for "A Multi-arm Phase 1b Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma" at ClinicalTrials.gov
  44. ↑ Clinical trial number NCT04126200 for "A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) - DREAMM 5" at ClinicalTrials.gov
  45. ↑ Hultcrantz M, Hassoun H, Tan CR, Korde N, Lesokhin AM, Hashmi H, et al. (5 November 2024). "Belantamab Mafodotin, nirogacestat and Pomalidomide for Patients with Relapsed/Refractory Multiple Myeloma". Blood. 144 (Supplement 1): 7077. doi:10.1182/blood-2024-211857. ISSN   0006-4971.
  46. ↑ Callander NS, Richardson PG, Hus M, Ribrag V, Lopez JM, Kim K, et al. (September 2023). "MM-533 Low-Dose Belantamab Mafodotin (Belamaf) in Combination With Nirogacestat Versus Belamaf Monotherapy in Patients With Relapsed/Refractory Multiple Myeloma (RRMM): Phase 1/2 DREAMM-5 Platform Sub-Study 3". Clinical Lymphoma, Myeloma & Leukemia. 23: S507 –S508. doi:10.1016/S2152-2650(23)01467-2.
  47. ↑ GlaxoSmithKline (1 January 2025). A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) - DREAMM 5 (Report). clinicaltrials.gov.
  48. ↑ Precision BioSciences, Inc. (18 September 2023). A Phase 1/2a, Open-label, Dose-escalation, Dose-expansion Study to Evaluate the Safety and Clinical Activity of PBCAR269A, With or Without Nirogacestat, in Study Participants With Relapsed/Refractory Multiple Myeloma (Report). clinicaltrials.gov.
  49. ↑ Shearer T, Comstock M, Williams RL, Johnson MC, Cendrowicz E, Leonowens C, et al. (11 December 2024). "Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma". Cancer Research Communications. 4 (12): 3114–3123. doi: 10.1158/2767-9764.crc-24-0075 . ISSN   2767-9764. PMC   11632591 . PMID   39530736.
  50. ↑ Shearer T, Williams RL, Johnson M, Cendrowicz E, Leonowens C, Smith M, et al. (15 November 2022). "Pharmacodynamic Effects of Nirogacestat, a Gamma Secretase Inhibitor, on B-Cell Maturation Antigen in Healthy Participants". Blood. 140 (Supplement 1): 3080–3081. doi: 10.1182/blood-2022-156811 . ISSN   0006-4971.
  51. ↑ Munawar U, Theuersbacher J, Steinhardt MJ, Zhou X, Han S, Nerreter S, et al. (4 April 2024). "Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma". Haematologica. 109 (11): 3670–3680. doi:10.3324/haematol.2024.285205. ISSN   1592-8721. PMC   11532697 . PMID   38572568.
  52. ↑ Papayannidis C, DeAngelo DJ, Stock W, Huang B, Shaik MN, Cesari R, et al. (September 2015). "A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma". Blood Cancer Journal. 5 (9): e350. doi: 10.1038/bcj.2015.80 . ISSN   2044-5385. PMC   4648526 . PMID   26407235.
  53. ↑ "Cellosaurus cell line HPB-ALL (CVCL_1820)". www.cellosaurus.org. Retrieved 22 July 2025.
  54. ↑ Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, et al. (1 June 2010). "Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design". Molecular Cancer Therapeutics. 9 (6): 1618–1628. doi:10.1158/1535-7163.MCT-10-0034. ISSN   1535-7163. PMID   20530712.
  55. ↑ Zhou Y, Guan L, Li W, Jia R, Jia L, Zhang Y, et al. (May 2022). "DT7 peptide-modified lecithin nanoparticles co-loaded with γ-secretase inhibitor and dexamethasone efficiently inhibit T-cell acute lymphoblastic leukemia and reduce gastrointestinal toxicity". Cancer Letters. 533: 215608. doi: 10.1016/j.canlet.2022.215608 . PMID   35240234.
  56. ↑ Zhou Y, Guan L, Li W, Jia R, Jia L, Zhang Y, et al. (May 2022). "DT7 peptide-modified lecithin nanoparticles co-loaded with γ-secretase inhibitor and dexamethasone efficiently inhibit T-cell acute lymphoblastic leukemia and reduce gastrointestinal toxicity". Cancer Letters. 533: 215608. doi: 10.1016/j.canlet.2022.215608 . PMID   35240234.
  57. ↑ Ehrmann AS, Quijada-Álamo M, Close V, Guo M, Carracoi V, Pérez-Carretero C, et al. (2 June 2025). "NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL". Leukemia: 1–13. doi: 10.1038/s41375-025-02632-4 . ISSN   1476-5551. PMID   40456839.
  58. ↑ Carrillo-Tornel S, Chen-Liang TH, Zurdo M, Puiggros A, Gómez-Llonín A, García-Malo MD, et al. (2023). "NOTCH1 mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle G1/S transition and specific cyclin overexpression: Preclinical ground for targeted inhibition". British Journal of Haematology. 201 (3): 470–479. doi: 10.1111/bjh.18609 . hdl: 10230/55947 . ISSN   1365-2141. PMID   36573331.
  59. ↑ Zhou N, Choi J, Grothusen G, Kim BJ, Ren D, Cao Z, et al. (14 September 2023). "DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance". Blood. 142 (11): 973–988. doi:10.1182/blood.2022018752. ISSN   0006-4971. PMC   10656726 . PMID   37235754.
  60. ↑ Dalton WT, Ahearn MJ, McCredie KB, Freireich EJ, Stass SA, Trujillo JM (January 1988). "HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3". Blood. 71 (1): 242–247. ISSN   0006-4971. PMID   3422031.
  61. ↑ "Cellosaurus cell line Kasumi-1 (CVCL_0589)". www.cellosaurus.org. Retrieved 25 July 2025.
  62. ↑ Quentmeier H, Pommerenke C, Dirks WG, Eberth S, Koeppel M, MacLeod RA, et al. (3 June 2019). "The LL-100 panel: 100 cell lines for blood cancer studies". Scientific Reports. 9 (1): 8218. doi:10.1038/s41598-019-44491-x. ISSN   2045-2322. PMC   6547646 . PMID   31160637.
  63. ↑ Láinez-González D, Serrano-López J, Llamas-Sillero P, Alonso-Dominguez JM (23 June 2022). "P420: FORCING LEUKAEMIC STEM CELL TO LEAVE QUIESCENT STATE BY INHIBITING HEDGEHOG, NOTCH AND WNT/BETA-CATENIN SIGNALLING PATHWAYS". HemaSphere. 6: 320–321. doi: 10.1097/01.HS9.0000844568.05214.d5 . ISSN   2572-9241.
  64. ↑ "Entry - 602582 - DELTEX E3 UBIQUITIN LIGASE 1; DTX1". omim.org. Retrieved 26 July 2025.
  65. ↑ "Entry 138040 - NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1; NR3C1". omim.org. Retrieved 26 July 2025.
  66. ↑ Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. (January 2009). "γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia". Nature Medicine. 15 (1): 50–58. doi:10.1038/nm.1900. ISSN   1078-8956. PMID   19098907.
  67. ↑ Samon JB, Castillo-Martin M, Hadler M, Ambesi-Impiobato A, Paietta E, Racevskis J, et al. (1 July 2012). "Preclinical Analysis of the γ-Secretase Inhibitor PF-03084014 in Combination with Glucocorticoids in T-cell Acute Lymphoblastic Leukemia". Molecular Cancer Therapeutics. 11 (7): 1565–1575. doi: 10.1158/1535-7163.MCT-11-0938 . ISSN   1535-7163. PMID   22504949.
  68. ↑ Aguirre SA, Liu L, Hosea NA, Scott W, May JR, Burns-Naas LA, et al. (January 2014). "Intermittent Oral Coadministration of a Gamma Secretase Inhibitor with Dexamethasone Mitigates Intestinal Goblet Cell Hyperplasia in Rats". Toxicologic Pathology. 42 (2): 422–434. doi: 10.1177/0192623313486315 . ISSN   0192-6233. PMID   23651588.
  69. ↑ Arribas A, Gaudio E, Arcaini L, Stathis A, Zucca E, Rossi D, et al. (2 December 2016). "Targeting the Epigenome and the Cell Signaling As Novel Therapeutic Approaches for Splenic Marginal Zone Lymphoma". Blood. 128 (22): 4186. doi: 10.1182/blood.v128.22.4186.4186 . ISSN   0006-4971.
  70. ↑ Shang H, Braggio D, Lee YJ, Al Sannaa GA, Creighton CJ, Bolshakov S, et al. (2015). "Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors". Cancer. 121 (22): 4088–4096. doi:10.1002/cncr.29564. ISSN   1097-0142. PMC   4635059 . PMID   26349011.
  71. ↑ Yabuuchi S, Pai SG, Campbell NR, de Wilde RF, De Oliveira E, Korangath P, et al. (July 2013). "Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer". Cancer Letters. 335 (1): 41–51. doi:10.1016/j.canlet.2013.01.054. PMC   3665739 . PMID   23402814.
  72. ↑ Pfizer (20 December 2018). PHASE 1/2 STUDY OF PF-03084014 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA (Report). clinicaltrials.gov.
  73. ↑ Wang S, Du L, Chen H, Zhang X, Chen B, Yang L (2021). "Paracrine production of IL-6 promotes a hypercoagulable state in pancreatic cancer". American Journal of Cancer Research. 11 (12): 5992–6003. ISSN   2156-6976. PMC   8727799 . PMID   35018238.
  74. ↑ Bousquet Mur E, Bernardo S, Papon L, Mancini M, Fabbrizio E, Goussard M, et al. (17 December 2019). "Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma". Journal of Clinical Investigation. 130 (2): 612–624. doi: 10.1172/JCI126896 . ISSN   0021-9738. PMC   6994195 . PMID   31671073.
  75. ↑ Wang ZJ, Zhan XY, Ma LY, Yao K, Dai HY, Kumar Santhanam R, et al. (December 2024). "Activation of the γ-secretase/NICD-PXR/Notch pathway induces Taxol resistance in triple-negative breast cancer" . Biochemical Pharmacology. 230 (Pt 2) 116577: 116577. doi:10.1016/j.bcp.2024.116577. PMID   39427919.
  76. ↑ Lessard CB, Rodriguez E, Ladd TB, Minter LM, Osborne BA, Miele L, et al. (July 2019). "Individual and combined presenilin 1 and 2 knockouts reveal that both have highly overlapping functions in HEK293T cells". The Journal of Biological Chemistry. 294 (29): 11276–11285. doi: 10.1074/jbc.RA119.008041 . PMC   6643044 . PMID   31167792.
  77. ↑ Dalton WT, Ahearn MJ, McCredie KB, Freireich EJ, Stass SA, Trujillo JM (January 1988). "HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3". Blood. 71 (1): 242–247. PMID   3422031.
  78. ↑ "Cellosaurus cell line Kasumi-1 (CVCL_0589)". www.cellosaurus.org. Retrieved 25 July 2025.
  79. ↑ Quentmeier H, Pommerenke C, Dirks WG, Eberth S, Koeppel M, MacLeod RA, et al. (June 2019). "The LL-100 panel: 100 cell lines for blood cancer studies". Scientific Reports. 9 (1): 8218. doi:10.1038/s41598-019-44491-x. PMC   6547646 . PMID   31160637.
  80. ↑ Láinez-González D, Serrano-López J, Llamas-Sillero P, Alonso-Dominguez JM (23 June 2022). "P420: FORCING LEUKAEMIC STEM CELL TO LEAVE QUIESCENT STATE BY INHIBITING HEDGEHOG, NOTCH AND WNT/BETA-CATENIN SIGNALLING PATHWAYS". HemaSphere. 6: 320–321. doi: 10.1097/01.HS9.0000844568.05214.d5 . ISSN   2572-9241.
  81. ↑ "Entry - 602582 - DELTEX E3 UBIQUITIN LIGASE 1; DTX1". omim.org. Retrieved 26 July 2025.
  82. ↑ "Entry 138040 - NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1; NR3C1". omim.org. Retrieved 26 July 2025.
  83. ↑ Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. (January 2009). "Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia". Nature Medicine. 15 (1): 50–58. doi:10.1038/nm.1900. PMID   19098907.
  84. ↑ Samon JB, Castillo-Martin M, Hadler M, Ambesi-Impiobato A, Paietta E, Racevskis J, et al. (July 2012). "Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia". Molecular Cancer Therapeutics. 11 (7): 1565–1575. doi: 10.1158/1535-7163.MCT-11-0938 . PMID   22504949.
  85. ↑ Aguirre SA, Liu L, Hosea NA, Scott W, May JR, Burns-Naas LA, et al. (January 2014). "Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats". Toxicologic Pathology. 42 (2): 422–434. doi: 10.1177/0192623313486315 . PMID   23651588.
  86. ↑ "Cellosaurus cell line MX-1 (CVCL_4774)". www.cellosaurus.org. Retrieved 22 July 2025.
  87. ↑ Zhang CC, Pavlicek A, Zhang Q, Lira ME, Painter CL, Yan Z, et al. (15 September 2012). "Biomarker and Pharmacologic Evaluation of the γ-Secretase Inhibitor PF-03084014 in Breast Cancer Models" . Clinical Cancer Research. 18 (18): 5008–5019. doi:10.1158/1078-0432.CCR-12-1379. ISSN   1078-0432. PMID   22806875.
  88. ↑ Means-Powell JA, Mayer IA, Ismail-Khan R, Valle LD, Tonetti D, Abramson VG, et al. (1 February 2022). "A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC)". Clinical Breast Cancer. 22 (2): 103–114. doi:10.1016/j.clbc.2021.10.013. ISSN   1526-8209. PMC   8821119 . PMID   34903452.
  89. ↑ Surendran V, Safarulla S, Griffith C, Ali R, Madan A, Polacheck W, et al. (11 September 2024). "Magnetically Integrated Tumor–Vascular Interface System to Mimic Pro-angiogenic Endothelial Dysregulations for On-Chip Drug Testing". ACS Applied Materials & Interfaces. 16 (36): 47075–47088. doi:10.1021/acsami.4c01766. ISSN   1944-8244. PMC   11403600 . PMID   39196896.
  90. ↑ SpringWorks Therapeutics, Inc. (2 August 2024). A Phase 2 Trial of Nirogacestat in Patients With Recurrent Ovarian Granulosa Cell Tumors (Report). clinicaltrials.gov.
  91. ↑ Chauvin MY, Pépin D (4 March 2024). "Abstract A023: Pre-clinical evaluation of the gamma-secretase inhibitor nirogacestat in an adult-type ovarian granulosa cell tumor model" . Cancer Research. 84 (5_Supplement_2): A023 –A023. doi: 10.1158/1538-7445.OVARIAN23-A023 . ISSN   1538-7445.
  92. ↑ Rivera IR, Sommerhalder D, Sahtout M, Ferlini C, Ngo D, Jha S, et al. (5 April 2024). "Abstract CT109: Livmoniplimab and budigalimab combination therapy in treating patients with metastatic ovarian granulosa cell tumors: Results from dose escalation in a first-in-human study". Cancer Research. 84 (7_Supplement): CT109. doi: 10.1158/1538-7445.am2024-ct109 . ISSN   0008-5472.
  93. ↑ Du Z, Li L, Sun W, Wang X, Zhang Y, Chen Z, et al. (July 2018). "HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro". International Journal of Oncology. 53 (1): 99–112. doi:10.3892/ijo.2018.4370. PMC   5958706 . PMID   29658567.
  94. ↑ Revandkar A, Perciato ML, Toso A, Alajati A, Chen J, Gerber H, et al. (December 2016). "Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence". Nature Communications. 7 (1): 13719. doi: 10.1038/ncomms13719 . PMID   27941799.
  95. ↑ Wu CX, Xu A, Zhang CC, Olson P, Chen L, Lee TK, et al. (August 2017). "Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3". Molecular Cancer Therapeutics. 16 (8): 1531–1543. doi: 10.1158/1535-7163.MCT-17-0001 . PMID   28522590.
  96. ↑ Yang X, Xia W, Chen L, Wu CX, Zhang CC, Olson P, et al. (October 2018). "Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma". Oncotarget. 9 (79): 34996–35007. doi: 10.18632/oncotarget.26209 . PMID   30405889.
  97. ↑ Zheng Y, Wang Z, Ding X, Dong Y, Zhang W, Zhang W, et al. (June 2018). "Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma". Cell Proliferation. 51 (3): e12424. doi: 10.1111/cpr.12424 . PMID   29232766.
  98. ↑ Zheng Y, Wang Z, Xiong X, Zhong Y, Zhang W, Dong Y, et al. (May 2019). "Membrane-tethered Notch1 exhibits oncogenic property via activation of EGFR-PI3K-AKT pathway in oral squamous cell carcinoma". Journal of Cellular Physiology. 234 (5): 5940–5952. doi:10.1002/jcp.27022. PMID   30515785.
  99. ↑ Porcelli L, Mazzotta A, Garofoli M, Di Fonte R, Guida G, Guida M, et al. (January 2021). "Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib". Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 133 111006: 111006. doi: 10.1016/j.biopha.2020.111006 . hdl: 11586/332834 . PMID   33202284.
  100. ↑ Ma W, Zhang J, Chen W, Liu N, Wu T (2025). "Notch-Driven Cholangiocarcinogenesis Involves the Hippo Pathway Effector TAZ via METTL3-m6A-YTHDF1". Cellular and Molecular Gastroenterology and Hepatology. 19 (1): 101417. doi:10.1016/j.jcmgh.2024.101417. PMC   11612812 . PMID   39369960.
  101. ↑ Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z, et al. (September 2019). "Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo" . Experimental Cell Research. 382 (1): 111470. doi:10.1016/j.yexcr.2019.06.015. PMID   31211955.
  102. ↑ Condorelli AG, Nobili R, Muglia A, Scarpelli G, Marzuolo E, De Stefanis C, et al. (July 2024). "Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa". The Journal of Investigative Dermatology. 144 (7): 1522–1533.e10. doi: 10.1016/j.jid.2023.10.045 . PMID   38237731.
  103. ↑ Idowu J, Home T, Patel N, Magenheimer B, Tran PV, Maser RL, et al. (20 February 2018). "Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease". Scientific Reports. 8 (1): 3340. doi: 10.1038/s41598-018-21132-3 . ISSN   2045-2322. PMC   5820265 . PMID   29463793.
  104. ↑ Momoh M, Roland J, Burman A, Brown M, Adeniran F, Ramos C, et al. (May 2024). "Distinct Treatment Outcomes between MVID Patient-Modeled Mice Suggest Epithelial Cell Maturation Is Influenced by MYO5B Functional State" . Physiology. 39 (S1). doi: 10.1152/physiol.2024.39.S1.2514 . ISSN   1548-9213.
  105. ↑ Du Y, Shen Y (February 2025). "Progress in photoreceptor replacement therapy for retinal degenerative diseases". Cell Insight. 4 (1): 100223. doi:10.1016/j.cellin.2024.100223. PMC   11773227 . PMID   39877255.
  106. ↑ Lee YK, Du W, Nie Y, Diaz B, Sultana N, Kitamoto T, et al. (December 2022). "Single-agent FOXO1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice". Molecular Metabolism. 66: 101618. doi:10.1016/j.molmet.2022.101618. PMC   9676376 . PMID   36283677.
  107. ↑ Pranaitytė G, Grybaitė B, Endriulaityte U, Mickevičius V, Petrikaitė V (21 May 2025). "Exploration of 1-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives effect on triple-negative breast, prostate cancer and melanoma cell 2D and 3D cultures". Scientific Reports. 15 (1): 17590. doi: 10.1038/s41598-025-02106-8 . ISSN   2045-2322. PMC   12095558 . PMID   40399317.
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