Navitoclax

Last updated
Navitoclax
Navitoclax.svg
Names
Preferred IUPAC name
4-(4-{{#parsoidfragment:0}}{[2-(4-Chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide
Other names
ABT263; ABT-263
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C47H55ClF3N5O6S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1
    Key: JLYAXFNOILIKPP-KXQOOQHDSA-N
  • InChI=1/C47H55ClF3N5O6S3/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57)/t38-/m1/s1
    Key: JLYAXFNOILIKPP-KXQOOQHDBT
  • CC1(CCC(=C(C1)CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(C=C4)N[C@H](CCN5CCOCC5)CSC6=CC=CC=C6)S(=O)(=O)C(F)(F)F)C7=CC=C(C=C7)Cl)C
Properties
C47H55ClF3N5O6S3
Molar mass 974.61 g·mol−1
Pharmacology
L01XX78 ( WHO )
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax. [1] [2]

Contents

Mechanism of action

In addition to Bcl-2, navitoclax also inhibits the related Bcl-xL and Bcl-w proteins. [3] Because navitoclax inhibits Bcl-xL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting. [4] [5] A 2020 article published in Aging Cell details the synthesis of Nav-Gal (navitoclax-galactose), a novel prodrug via galacto-conjugation of navitoclax and its superiority. The prodrug reduces thrombocytopenia in treated mice at therapeutically effective doses, as well as apoptosis of platelets in human blood samples treated ex vivo. Nav-Gal is efficient for selective senolysis and is passively taken up by both non-senescent and senescent cells. [6]

Effects against senescent cells

In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells. [7] Oral administration of navitoclax (ABT-263) to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice. [8]

On September 19, 2018, an article was published in Nature about using navitoclax to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's disease. [9]

On December 3, 2024, an article was published in Aging detailing a study investigating the effects of topical navitoclax (ABT-263) on aged mouse skin. It examined whether eliminating senescent cells could improve wound healing. In the study, 24-month-old mice were treated with topical navitoclax (ABT-263) for five days. The treatment reduced the expression of senescence markers p16 and p21 and decreased the number of SA-β-gal– and p21-positive cells compared with DMSO controls. Navitoclax (ABT-263) application also induced a transient inflammatory response and macrophage infiltration. Bulk RNA sequencing revealed upregulation of genes involved in wound-healing pathways, including inflammation, angiogenesis, collagen synthesis, and extracellular matrix remodeling. Mice pre-treated with navitoclax (ABT-263) exhibited faster wound closure, suggesting that topical senolytic treatment may enhance skin repair by reducing senescent cell burden. [10]

Clinical trials

The drug is currently under development by AbbVie.

Navitoclax is used as mono-therapy [11] [12] as well as in combination with chemotherapies (paclitaxel, docetaxel, gemcitabine, and irinotecan), olaparib, [13] erlotinib, [14] venetoclax, [15] and rituximab [16] in advanced hematological malignancies (in both pediatric and adult patients) and solid tumors including ovarian cancer, breast cancer, lung cancer.

Additionally, an ongoing global multi-center, randomized, open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination with ruxolitinib versus best available therapy in adult patients with relapsed/refractory myelofibrosis was initiated on 31 August, 2020. The study is expected to conclude in 2026. [17]

Antisclerotic

Not directly related to cancer, rather as a therapy for scleroderma, navitoclax appeared to reduce existing fibrosis through inducing apoptosis of myofibroblasts. [18] Further research is required to elucidate the exact mechanisms and confirm studies.

References

  1. ↑ Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (March 2011). "Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors". Journal of Clinical Oncology. 29 (7): 909–16. doi:10.1200/JCO.2010.31.6208. PMC   4668282 . PMID   21282543.
  2. ↑ Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. (March 2015). "Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy". Science Translational Medicine. 7 (279): 279ra40. doi:10.1126/scitranslmed.aaa4642. PMID   25787766. S2CID   206686917.
  3. ↑ Chen, J.; Jin, S.; Abraham, V.; Huang, X.; Liu, B.; Mitten, M. J.; Nimmer, P.; Lin, X.; Smith, M.; Shen, Y.; Shoemaker, A. R.; Tahir, S. K.; Zhang, H.; Ackler, S. L.; Rosenberg, S. H.; Maecker, H.; Sampath, D.; Leverson, J. D.; Tse, C.; Elmore, S. W. (2011). "The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo". Molecular Cancer Therapeutics. 10 (12). Mol Cancer Ther. 2011 Dec;10(12):2340-9. doi: 10.1158/1535-7163.MCT-11-0415. Epub 2011 Sep 13.: 2340–9. doi: 10.1158/1535-7163.MCT-11-0415 . PMID   21914853.
  4. ↑ Roberts, A. W.; Wilson, W.; Gandhi, L.; O'Connor, O. A.; Rudin, C. M.; Brown, J. R.; Xiong, H.; Chiu, Y.; Enschede, S.; Krivoshik, A. P. (2009-05-20). "Ongoing phase I studies of ABT-263: Mitigating Bcl-XL induced thrombocytopenia with lead-in and continuous dosing". Journal of Clinical Oncology. 27 (15_suppl): 3505–3505. doi:10.1200/jco.2009.27.15_suppl.3505. ISSN   0732-183X.
  5. ↑ Gandhi, Leena; Camidge, D. Ross; Ribeiro de Oliveira, Moacyr; Bonomi, Philip; Gandara, David; Khaira, Divis; Hann, Christine L.; McKeegan, Evelyn M.; Litvinovich, Elizabeth; Hemken, Philip M.; Dive, Caroline; Enschede, Sari H.; Nolan, Cathy; Chiu, Yi-Lin; Busman, Todd (2011-03-01). "Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 29 (7): 909–916. doi:10.1200/JCO.2010.31.6208. ISSN   1527-7755. PMC   4668282 . PMID   21282543.
  6. ↑ González-Gualda, Estela; Pàez-Ribes, Marta; Lozano-Torres, Beatriz; Macias, David; Wilson, Joseph R.; González-López, Cristina; Ou, Hui-Ling; Mirón-Barroso, Sofía; Zhang, Zhenguang; Lérida-Viso, Araceli; Blandez, Juan F.; Bernardos, Andrea; Sancenón, Félix; Rovira, Miguel; Fruk, Ljiljana. "Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity". Aging Cell. 19 (4): e13142. doi:10.1111/acel.13142. ISSN   1474-9726. PMC   7189993 . PMID   32233024.{{cite journal}}: CS1 maint: article number as page number (link)
  7. ↑ Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. (June 2016). "Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors". Aging Cell. 15 (3): 428–35. doi:10.1111/acel.12445. PMC   4854923 . PMID   26711051.
  8. ↑ Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (January 2016). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22 (1): 78–83. doi:10.1038/nm.4010. PMC   4762215 . PMID   26657143.
  9. ↑ Bussian, Tyler J.; Aziz, Asef; Meyer, Charlton F.; Swenson, Barbara L.; van Deursen, Jan M.; Baker, Darren J. (October 2018). "Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline". Nature. 562 (7728): 578–582. Bibcode:2018Natur.562..578B. doi:10.1038/s41586-018-0543-y. ISSN   1476-4687. PMC   6206507 . PMID   30232451.
  10. ↑ Shvedova, Maria; Thanapaul, Rex Jeya Rajkumar Samdavid; Ha, Joy; Dhillon, Jannat; Shin, Grace H.; Crouch, Jack; Gower, Adam C.; Gritli, Sami; Roh, Daniel S. (2024-12-03). "Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing". Aging. 17 (1): 16–32. doi:10.18632/aging.206165. ISSN   1945-4589. PMID   39630941.
  11. ↑ Roberts, Andrew (10 February 2012). "Substantial Susceptibility of to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease". Journal of Clinical Oncology. 30 (5): 488–496. doi:10.1200/jco.2011.34.7898. PMC   4979082 . PMID   22184378.
  12. ↑ Joly, Florence (2022). "A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI - GINECO study". Gynecologic Oncology. 165 (1): 30–39. doi: 10.1016/j.ygyno.2022.01.021 . PMID   35123771. S2CID   246499398.
  13. ↑ Mackay, Helen (June 2023). "Exactis-03: A phase I trial of the combination of olaparib and navitoclax in women with high grade serous ovarian cancer and triple negative" . Journal of Clinical Oncology. 41 (16_suppl) TPS5623. doi:10.1200/JCO.2023.41.16_suppl.TPS5623. S2CID   259080754.
  14. ↑ Tolcher, Anthony (2015). "Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with in patients with advanced solid tumors. Cancer Chemother Pharmacol". Cancer Chemotherapy and Pharmacology. 76 (5): 1025–1032. doi:10.1007/s00280-015-2883-8. PMID   26420235. S2CID   23878408.
  15. ↑ Pullarkat, Vinod (2021). "Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory and Lymphoblastic Lymphoma". Cancer Discovery. 11 (6): 1440–1453. doi: 10.1158/2159-8290.CD-20-1465 . PMC   9533326 . PMID   33593877.
  16. ↑ Kipps, Thomas (2015). "A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without , in previously untreated B-cell chronic lymphocytic leukemia". Leukemia & Lymphoma. 56 (10): 2826–2833. doi:10.3109/10428194.2015.1030638. PMC   4643417 . PMID   25797560.
  17. ↑ AbbVie (2025-04-22). Randomized, Open-Label, Phase 3 Study Evaluating Efficacy and Safety of Navitoclax in Combination With Ruxolitinib Versus Best Available Therapy in Subjects With Relapsed/Refractory Myelofibrosis (TRANSFORM-2), Incorporating Extension Arm C - Continued Access for Navitoclax to Roll Over Subjects From Studies M10-166, M16-109, M16-191, and M19-753 (Report). clinicaltrials.gov.
  18. ↑ Lagares, David; Santos, Alba; Grasberger, Paula E.; Liu, Fei; Probst, Clemens K.; Rahimi, Rod A.; Sakai, Norihiko; Kuehl, Tobias; Ryan, Jeremy; Bhola, Patrick; Montero, Joan; Kapoor, Mohit; Baron, Murray; Varelas, Xaralabos; Tschumperlin, Daniel J. (2017-12-13). "Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis". Science Translational Medicine. 9 (420): eaal3765. doi:10.1126/scitranslmed.aal3765. ISSN   1946-6242. PMC   8520471 . PMID   29237758.{{cite journal}}: CS1 maint: article number as page number (link)
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