Bomedemstat

Last updated
Bomedemstat
Bomedemstat.svg
Clinical data
Other namesIMG-7289
Identifiers
  • N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(triazol-1-yl)benzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C28H34FN7O2
Molar mass 519.625 g·mol−1
3D model (JSmol)
  • CN1CCN(CC1)C(=O)[C@H](CCCN[C@@H]2C[C@H]2C3=CC=C(C=C3)F)NC(=O)C4=CC=C(C=C4)N5C=CN=N5
  • InChI=1S/C28H34FN7O2/c1-34-15-17-35(18-16-34)28(38)25(3-2-12-30-26-19-24(26)20-4-8-22(29)9-5-20)32-27(37)21-6-10-23(11-7-21)36-14-13-31-33-36/h4-11,13-14,24-26,30H,2-3,12,15-19H2,1H3,(H,32,37)/t24-,25-,26+/m0/s1
  • Key:KQKBMHGOHXOHTD-KKUQBAQOSA-N

Bomedmestat (USAN; IUPAC name N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(triazol-1-yl)benzamide) is an investigational drug under development by Imago BioSciences for the treatment of myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and myelofibrosis. [1]

Contents

History

Bomedmestat, also known as IMG-7289 or MRK3543, the bis-tosylate salt of IMG-241 MRK3543, was invented by Hugh Young Rienhoff, Jr, Michael Clare, Amy Tapper and John McCall in 2014. The original composition-of-matter patent application was filed in 2014. [2] and issued as US patent US-20150299151-A1 followed by other issued patents on polymorphs, salt forms and methods of manufacture.

Merck (Merck Sharp and Dohme) acquired Imago BioSciences with the rights to develop bomedemstat in January 2023.

Mechanism of action

Bomedemstat was developed to inhibit the human enzyme lysine-specific demethylase-1 (LSD1 or KDM1A EC:1.14.99.66), an oxidating enzyme that mediates demethylation of lysine 4 of histone H3 (H3K4) mono- and di-methyl (H3K4me1 and H3K4me2), modifications known as epigenetics marks; histone H3 H3K4me1/m2 marks are generally associated with repression of DNA transcription. Identified as a histone demethylase in 2004, LSD1 demethylates H3K4me1 and H3K4me2 but not tri-methylated H3K4. [3] [4] [5] [6] Other methylated protein substrates of LSD1 have been reported but their physiologic or pathologic significance have not yet been biochemically validated.

Bomedemstat is an irreversible inhibitor of LSD1, a protein that coordinates flavine adenine dinucleotide (FAD), a co-factor essential for the oxidative demethylation reaction. The first step in the catalytic reaction of LSD1 involves the abstraction of hydride from the target methyl of the H3K4 sidechain N-methyl by the oxidized state of a non-covalently bound FAD prosthetic group at the LSD1 active site to give a stabilized methylene iminium ion. This is then hydrolyzed by a water molecule to give an unstable vicinal terminal hydroxyl amine which rapidly decomposes to yield the de-methylated lysine H3K4 molecule and formaldehyde, which diffuses away and is subsequently metabolized by aldehyde dehydrogenase. The now-reduced FAD at the active site reacts with a molecule of oxygen forming a covalent mono-hydroperoxide adduct which is then hydrolyzed by water to yield hydrogen peroxide, and in so doing regenerates the more stable FAD oxidized (resting) state. A highly conserved lysine (Lys661 in LSD1) at the active site in FAD-dependent amine oxidases is believed to assist in this reaction. The overall reaction stoichiometry thus involves the conversion of an N-methyl group by water and oxygen to give molecules of formaldehyde, hydrogen peroxide, and the product N-H terminus.

LSD1 cannot demethylate H3K4 trimethyl (N-tri-methyl-lysine) because the initial iminium species cannot be formed owing to a lack of an available lone electron pair at the N-center, essential for formation of the requisite stabilizing pi-system.

In the irreversible inhibition of LSD1 by bomedemstat, the initial hydride abstraction event by the oxidized FAD center targets the free cyclopropyl methylene generating an unstable carbo-cation which rapidly rearranges to form an unbound but stabilized conjugated iminium cation intermediate. That species is then hydrolytically cleaved by water to give free amine and cinnamaldehyde fragments. The reduced FAD state is converted back to its normal resting oxidized state by molecular oxygen with the production of hydrogen peroxide while the larger cinnamaldehyde fragment, rather than diffusing away from the active site, is able to react in situ with the oxidized FAD to form a stable covalent adduct, effectively locking the LSD1/CoREST complex into a permanently inactivated state.

Research

After extensive pre-clinical testing, San Francisco-based Imago BioSciences sponsored the first human trial of bomedemstat in 2016 for the treatment of high-risk myelodysplastic syndrome and acute myeloid leukemia (AML) that was either refractory to available therapies or relapsed from treatment. [7] The study was conducted entirely in Australia. A second Imago-sponsored clinical study of bomedemstat was begun in patients with myelofibrosis who had failed the standard-of-care treatment. [8] The results of this global study have been presented at the American Society of Hematology, the European Hematology Association and other important forums of hematologic research. A third Imago-sponsored global clinical trial for the treatment of essential thrombocythemia was begun in 2020. [9] The results of this global study have also been presented at the American Society of Hematology and the European Hematology Association. A fourth trial begun in 2023 for the treatment of polycythemia vera is ongoing. [10]

Several other investigator-initiated studies of bomedemstat either as monotherapy or in combination with other agents for hematologic malignancies or solid tumors are underway.

Related Research Articles

Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms.

<span class="mw-page-title-main">Tranylcypromine</span> Irreversible non-selective MAO inhibitor Antidepressant drug

Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

<span class="mw-page-title-main">Thrombocythemia</span> Medical condition

Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L.

<span class="mw-page-title-main">Essential thrombocythemia</span> Medical condition

Essential thrombocythemia (ET) is a rare chronic blood cancer characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of the myeloproliferative neoplasm wherein the bone marrow produces too many white or red blood cells, or platelets.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL gene markers. In PMF, the healthy marrow is replaced by scar tissue (fibrosis), resulting in a lack of production of normal blood cells. Symptoms include anemia, increased infection and an enlarged spleen (splenomegaly).

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Medical condition

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genome by controlling the methylation of DNA and histones, and by extension, the chromatin state at specific gene loci.

<span class="mw-page-title-main">PHD finger</span>

The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the plant homeodomain proteins HAT3.1 in Arabidopsis and maize ZmHox1a. The PHD zinc finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain and the bromodomain.

<span class="mw-page-title-main">KDM1A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.

<span class="mw-page-title-main">UTX (gene)</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), is a protein which in humans is encoded by the KDM6A gene. It belongs to the 2-oxoglutarate (2OG)-dependent dioxygenase superfamily.

Givinostat (INN) or gavinostat is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a hydroxamate used in the form of its hydrochloride.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Momelotinib</span> Chemical compound

Momelotinib (INN, formerly GS-0387, CYT-387) is an inhibitor of Janus kinases JAK1 and JAK2, acting as an ATP competitor with IC50 values of 11 and 18 nM, respectively. The inhibitor is significantly less active towards other kinases, including JAK3 (IC50 = 0.16 μM).

(Histone-H3)-lysine-36 demethylase (EC 1.14.11.27, JHDM1A, JmjC domain-containing histone demethylase 1A, H3-K36-specific demethylase, histone-lysine (H3-K36) demethylase, histone demethylase, protein-6-N,6-N-dimethyl-L-lysine,2-oxoglutarate:oxygen oxidoreductase) is an enzyme with systematic name protein-N6,N6-dimethyl-L-lysine,2-oxoglutarate:oxygen oxidoreductase. This enzyme catalyses the following chemical reaction

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

<span class="mw-page-title-main">KDM1B</span> Protein-coding gene in the species Homo sapiens

Lysine (K)-specific demethylase 1B is a protein that in humans is encoded by the KDM1B gene.

<span class="mw-page-title-main">Gandotinib</span> Chemical compound

Gandotinib (LY-2784544) is an experimental drug developed by Eli Lilly for treatment of cancer. It is a small molecule JAK2 inhibitor, with additional minor inhibition of STAT3.

<span class="mw-page-title-main">Tazemetostat</span> Chemical compound

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References

  1. ↑ "Bomedemstat". PubChem. U.S. National Library of Medicine.
  2. ↑ WO 2014164867,Mccall J, Rienhoff H, Clare M,"KDM1A inhibitors for the treatment of disease",published 9 October 2014, assigned to Imago Biosciences.
  3. ↑ Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. (December 2004). "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell. 119 (7): 941–953. doi:10.1016/j.cell.2004.12.012. PMID   15620353. S2CID   10847230.
  4. ↑ Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, et al. (June 2010). "The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1". The EMBO Journal. 29 (11): 1803–1816. doi:10.1038/emboj.2010.63. PMC   2885925 . PMID   20389281.
  5. ↑ Baron R, Binda C, Tortorici M, McCammon JA, Mattevi A (February 2011). "Molecular mimicry and ligand recognition in binding and catalysis by the histone demethylase LSD1-CoREST complex". Structure. 19 (2): 212–220. doi:10.1016/j.str.2011.01.001. PMC   3059804 . PMID   21300290.
  6. ↑ Tortorici M, Borrello MT, Tardugno M, Chiarelli LR, Pilotto S, Ciossani G, et al. (August 2013). "Protein recognition by short peptide reversible inhibitors of the chromatin-modifying LSD1/CoREST lysine demethylase". ACS Chemical Biology. 8 (8): 1677–1682. doi:10.1021/cb4001926. PMID   23721412.
  7. ↑ Clinical trial number NCT02842827 for "IMG-7289, With and Without ATRA, in Patients With Advanced Myeloid Malignancies" at ClinicalTrials.gov
  8. ↑ Clinical trial number NCT03136185 for "IMG-7289 in Patients With Myelofibrosis" at ClinicalTrials.gov
  9. ↑ Clinical trial number NCT04254978 for "Study of Bomedemstat in Participants With Essential Thrombocythemia (IMG-7289-CTP-201/MK-3543-003)" at ClinicalTrials.gov
  10. ↑ Clinical trial number NCT05558696 for "Bomedemstat in Patients With Polycythemia Vera" at ClinicalTrials.gov
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