MedKoo product information:

 Obatoclax

Description of Obatoclax mesylate: Obatoclax mesylate is the mesylate salt of obatoclax, a synthetic small-molecule inhibitor of the bcl-2 family of proteins with potential pro-apoptotic and antineoplastic activities. Obatoclax binds to members of the Bcl-2 protein family, preventing the binding of these anti-apoptotic proteins to the pro-apoptotic proteins Bax and Bak and so promoting the activation of the apoptotic pathway in Bcl-2-overexpressing cells. The Bcl-2 family of proteins (bcl-2, bcl-xl, bcl-w, and Mcl-1) are overexpressed in a wide variety of cancers, including those of the lymphatic system, breast, lung, prostate, and colon. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Gemin X.

Obatoclax is an experimental drug candidate for the treatment of various types of cancer. It was discovered by Gemin X, which was acquired by Cephalon.  It is in Phase II clinical trials for the treatment of leukemia, lymphoma, myelofibrosis, and mastocytosis. Obatoclax is an inhibitor of the Bcl-2 family of proteins. This inhibition induces apoptosis in cancer cells, preventing tumor growth.

1: Díaz de Greñu B, Hernández PI, Espona M, Quiñonero D, Light ME, Torroba T, Pérez-Tomás R, Quesada R. Synthetic Prodiginine Obatoclax (GX15-070) and Related Analogues: Anion Binding, Transmembrane Transport, and Cytotoxicity Properties. Chemistry. 2011 Nov 9. doi: 10.1002/chem.201101547. [Epub ahead of print] PubMed PMID: 22069220.

2: Lieber J, Ellerkamp V, Wenz J, Kirchner B, Warmann SW, Fuchs J, Armeanu-Ebinger S. Apoptosis sensitizers enhance cytotoxicity in hepatoblastoma cells. Pediatr Surg Int. 2011 Oct 5. [Epub ahead of print] PubMed PMID: 21971946.

3: Martínez-Paniagua MA, Baritaki S, Huerta-Yepez S, Ortiz-Navarrete VF, González-Bonilla C, Bonavida B, Vega MI. Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15-070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis. Cell Cycle. 2011 Aug 15;10(16):2792-805. Epub 2011 Aug 15. PubMed PMID: 21822052.

4: Jóna A, Khaskhely N, Buglio D, Shafer JA, Derenzini E, Bollard CM, Medeiros LJ, Illés A, Ji Y, Younes A. The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Exp Hematol. 2011 Oct;39(10):1007-1017.e1. doi: 10.1016/j.exphem.2011.07.002. Epub 2011 Jul 20. PubMed PMID: 21767511; PubMed Central PMCID: PMC3177003.

5: Acoca S, Cui Q, Shore GC, Purisima EO. Molecular dynamics study of small molecule inhibitors of the Bcl-2 family. Proteins. 2011 Sep;79(9):2624-36. doi: 10.1002/prot.23083. Epub 2011 Jun 30. PubMed PMID: 21721047.

6: Herishanu Y, Gibellini F, Njuguna N, Hazan-Halevy I, Farooqui M, Bern S, Keyvanfar K, Lee E, Wilson W, Wiestner A. Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. Leuk Lymphoma. 2011 Sep;52(9):1758-69. Epub 2011 Jun 8. PubMed PMID: 21649540.

7: Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, Travis W, James L, Ginsberg MS, Juergens R, Markus S, Tyson L, Subzwari S, Kris MG, Krug LM. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011 Dec;74(3):481-5. Epub 2011 May 26. PubMed PMID: 21620511.

8: Brem EA, Thudium K, Khubchandani S, Tsai PC, Olejniczak SH, Bhat S, Riaz W, Gu J, Iqbal A, Campagna R, Knight J, Mavis C, Hoskin P, Deeb G, Gibbs JF, Fetterly G, Czuczman MS, Hernandez-Ilizaliturri FJ. Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol. 2011 Jun;153(5):599-611. doi: 10.1111/j.1365-2141.2011.08669.x. Epub 2011 Apr 15. PubMed PMID: 21492126; PubMed Central PMCID: PMC3092002.

9: Dean EJ, Cummings J, Roulston A, Berger M, Ranson M, Blackhall F, Dive C. Optimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer. Neoplasia. 2011 Apr;13(4):339-47. PubMed PMID: 21472138; PubMed Central PMCID: PMC3071082.

10: Heidari N, Hicks MA, Harada H. GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy. Cell Death Dis. 2010 Sep 16;1:e76. PubMed PMID: 21364679; PubMed Central PMCID: PMC3032343.

11: Abou-Nassar K, Brown JR. Novel agents for the treatment of chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2010 Dec;8(12):886-95. Review. PubMed PMID: 21326166.

12: Crawford N, Chacko AD, Savage KI, McCoy F, Redmond K, Longley DB, Fennell DA. Platinum resistant cancer cells conserve sensitivity to BH3 domains and obatoclax induced mitochondrial apoptosis. Apoptosis. 2011 Mar;16(3):311-20. PubMed PMID: 21107700.

13: Bourquin JP, Bornhauser B. Have chemosensitizing strategies for multidrug-resistant childhood acute lymphoblastic leukemia come of age? Expert Rev Hematol. 2010 Aug;3(4):369-72. PubMed PMID: 21083025.

14: Mitchell C, Yacoub A, Hossein H, Martin AP, Bareford MD, Eulitt P, Yang C, Nephew KP, Dent P. Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Biol Ther. 2010 Nov 23;10(9):903-17. Epub 2010 Nov 1. PubMed PMID: 20855960; PubMed Central PMCID: PMC3040858.

15: Samuel S, Tumilasci VF, Oliere S, Nguyên TL, Shamy A, Bell J, Hiscott J. VSV oncolysis in combination with the BCL-2 inhibitor obatoclax overcomes apoptosis resistance in chronic lymphocytic leukemia. Mol Ther. 2010 Dec;18(12):2094-103. Epub 2010 Sep 14. PubMed PMID: 20842105; PubMed Central PMCID: PMC2997588.

16: Leber B, Geng F, Kale J, Andrews DW. Drugs targeting Bcl-2 family members as an emerging strategy in cancer. Expert Rev Mol Med. 2010 Sep 8;12:e28. Review. PubMed PMID: 20822554.

17: Wei Y, Kadia T, Tong W, Zhang M, Jia Y, Yang H, Hu Y, Viallet J, O'Brien S, Garcia-Manero G. The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Autophagy. 2010 Oct;6(7):976-8. Epub 2010 Oct 23. PubMed PMID: 20729640.

18: Parikh SA, Kantarjian H, Schimmer A, Walsh W, Asatiani E, El-Shami K, Winton E, Verstovsek S. Phase II study of obatoclax mesylate (GX15-070), a small-molecule BCL-2 family antagonist, for patients with myelofibrosis. Clin Lymphoma Myeloma Leuk. 2010 Aug 1;10(4):285-9. PubMed PMID: 20709666.

19: Hwang JJ, Kuruvilla J, Mendelson D, Pishvaian MJ, Deeken JF, Siu LL, Berger MS, Viallet J, Marshall JL. Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-BCL-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 2010 Aug 1;16(15):4038-45. Epub 2010 Jun 10. PubMed PMID: 20538761.

20: Wei Y, Kadia T, Tong W, Zhang M, Jia Y, Yang H, Hu Y, Tambaro FP, Viallet J, O'Brien S, Garcia-Manero G. The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy. Clin Cancer Res. 2010 Aug 1;16(15):3923-32. Epub 2010 Jun 10. PubMed PMID: 20538760.

21: Campbell CJ, Lee JB, Levadoux-Martin M, Wynder T, Xenocostas A, Leber B, Bhatia M. The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity. Blood. 2010 Sep 2;116(9):1433-42. Epub 2010 Jun 4. PubMed PMID: 20525924.

22: Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov. 2010 Jun;9(6):447-64. Epub 2010 May 14. Review. PubMed PMID: 20467424.

23: Pérez-Tomás R, Viñas M. New insights on the antitumoral properties of prodiginines. Curr Med Chem. 2010;17(21):2222-31. Review. PubMed PMID: 20459382.

24: Lin TS. New agents in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2010 Jan;5(1):29-34. Review. PubMed PMID: 20425394.

25: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2010 Jan-Feb;32(1):47-86. PubMed PMID: 20383346.

26: Bonapace L, Bornhauser BC, Schmitz M, Cario G, Ziegler U, Niggli FK, Schäfer BW, Schrappe M, Stanulla M, Bourquin JP. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest. 2010 Apr 1;120(4):1310-23. PubMed PMID: 20200450; PubMed Central PMCID: PMC2846044.

27: Paik PK, Rudin CM, Brown A, Rizvi NA, Takebe N, Travis W, James L, Ginsberg MS, Juergens R, Markus S, Tyson L, Subzwari S, Kris MG, Krug LM. A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemother Pharmacol. 2010 Nov;66(6):1079-85. Epub 2010 Feb 18. PubMed PMID: 20165849; PubMed Central PMCID: PMC2945625.

28: Smoot RL, Blechacz BR, Werneburg NW, Bronk SF, Sinicrope FA, Sirica AE, Gores GJ. A Bax-mediated mechanism for obatoclax-induced apoptosis of cholangiocarcinoma cells. Cancer Res. 2010 Mar 1;70(5):1960-9. Epub 2010 Feb 16. PubMed PMID: 20160031; PubMed Central PMCID: PMC2831099.

29: Pan J, Cheng C, Verstovsek S, Chen Q, Jin Y, Cao Q. The BH3-mimetic GX15-070 induces autophagy, potentiates the cytotoxicity of carboplatin and 5-fluorouracil in esophageal carcinoma cells. Cancer Lett. 2010 Jul 28;293(2):167-74. Epub 2010 Feb 13. PubMed PMID: 20153924.

30: McCoy F, Hurwitz J, McTavish N, Paul I, Barnes C, O'Hagan B, Odrzywol K, Murray J, Longley D, McKerr G, Fennell DA. Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK. Cell Death Dis. 2010 Dec 16;1:e108. PubMed PMID: 21368880; PubMed Central PMCID: PMC3032298.

31: Amaravadi R. Autophagy can contribute to cell death when combining targeted therapy. Cancer Biol Ther. 2009 Nov;8(21):130-3. Epub 2009 Nov 26. PubMed PMID: 19901522.

32: Aichberger KJ, Gleixner KV, Mirkina I, Cerny-Reiterer S, Peter B, Ferenc V, Kneidinger M, Baumgartner C, Mayerhofer M, Gruze A, Pickl WF, Sillaber C, Valent P. Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. Blood. 2009 Dec 17;114(26):5342-51. Epub 2009 Oct 22. PubMed PMID: 19850739.

33: Martin AP, Mitchell C, Rahmani M, Nephew KP, Grant S, Dent P. Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. Cancer Biol Ther. 2009 Nov;8(21):2084-96. Epub 2009 Nov 21. PubMed PMID: 19823038.

34: Hurwitz JL, McCoy F, Scullin P, Fennell DA. New advances in the second-line treatment of small cell lung cancer. Oncologist. 2009 Oct;14(10):986-94. Epub 2009 Oct 9. Review. PubMed PMID: 19819917.

35: Jiang CC, Wroblewski D, Yang F, Hersey P, Zhang XD. Human melanoma cells under endoplasmic reticulum stress are more susceptible to apoptosis induced by the BH3 mimetic obatoclax. Neoplasia. 2009 Sep;11(9):945-55. PubMed PMID: 19724688; PubMed Central PMCID: PMC2735806.

36: Hutcheson J, Perlman H. BH3-only proteins in rheumatoid arthritis: potential targets for therapeutic intervention. Oncogene. 2008 Dec;27 Suppl 1:S168-75. Review. PubMed PMID: 19641502; PubMed Central PMCID: PMC2838494.

37: Chonghaile TN, Letai A. Mimicking the BH3 domain to kill cancer cells. Oncogene. 2008 Dec;27 Suppl 1:S149-57. Review. PubMed PMID: 19641500.

38: Martin AP, Park MA, Mitchell C, Walker T, Rahmani M, Thorburn A, Häussinger D, Reinehr R, Grant S, Dent P. BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing. Mol Pharmacol. 2009 Aug;76(2):327-41. Epub 2009 May 29. PubMed PMID: 19483105; PubMed Central PMCID: PMC2713125.

39: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Mar;31(2):107-46. PubMed PMID: 19455266.

40: Vogler M, Weber K, Dinsdale D, Schmitz I, Schulze-Osthoff K, Dyer MJ, Cohen GM. Different forms of cell death induced by putative BCL2 inhibitors. Cell Death Differ. 2009 Jul;16(7):1030-9. Epub 2009 Apr 24. PubMed PMID: 19390557.

41: Cheson BD. Novel therapies for peripheral T-cell non-Hodgkin's lymphomas. Curr Opin Hematol. 2009 Jul;16(4):299-305. Review. PubMed PMID: 19367159.

42: López-Guerra M, Roué G, Pérez-Galán P, Alonso R, Villamor N, Montserrat E, Campo E, Colomer D. p65 activity and ZAP-70 status predict the sensitivity of chronic lymphocytic leukemia cells to the selective IkappaB kinase inhibitor BMS-345541. Clin Cancer Res. 2009 Apr 15;15(8):2767-76. Epub 2009 Apr 7. PubMed PMID: 19351760.

43: Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009 Feb 15;15(4):1126-32. Review. PubMed PMID: 19228717; PubMed Central PMCID: PMC3182268.

44: Huang S, Okumura K, Sinicrope FA. BH3 mimetic obatoclax enhances TRAIL-mediated apoptosis in human pancreatic cancer cells. Clin Cancer Res. 2009 Jan 1;15(1):150-9. PubMed PMID: 19118042; PubMed Central PMCID: PMC2948485.

45: Schimmer AD, O'Brien S, Kantarjian H, Brandwein J, Cheson BD, Minden MD, Yee K, Ravandi F, Giles F, Schuh A, Gupta V, Andreeff M, Koller C, Chang H, Kamel-Reid S, Berger M, Viallet J, Borthakur G. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res. 2008 Dec 15;14(24):8295-301. PubMed PMID: 19088047.

46: Lin TS. Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies. Clin Lymphoma Myeloma. 2008 Aug;8 Suppl 4:S137-43. Review. PubMed PMID: 18952544.

47: O'Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, Viallet J, Cheson BD. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009 Jan 8;113(2):299-305. Epub 2008 Oct 17. PubMed PMID: 18931344.

48: Azmi AS, Mohammad RM. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J Cell Physiol. 2009 Jan;218(1):13-21. Review. PubMed PMID: 18767026; PubMed Central PMCID: PMC2577714.

49: Mott JL, Bronk SF, Mesa RA, Kaufmann SH, Gores GJ. BH3-only protein mimetic obatoclax sensitizes cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis. Mol Cancer Ther. 2008 Aug;7(8):2339-47. PubMed PMID: 18723481; PubMed Central PMCID: PMC2562222.

50: Marzo I, Naval J. Bcl-2 family members as molecular targets in cancer therapy. Biochem Pharmacol. 2008 Oct 15;76(8):939-46. Epub 2008 Jun 28. PubMed PMID: 18638457.

51: Pérez-Galán P, Roué G, López-Guerra M, Nguyen M, Villamor N, Montserrat E, Shore GC, Campo E, Colomer D. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia. 2008 Sep;22(9):1712-20. Epub 2008 Jul 3. PubMed PMID: 18596739.

52: Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, Bornmann W, Kantarjian H, Viallet J, Samudio I, Andreeff M. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 2008 May 1;68(9):3413-20. PubMed PMID: 18451169.

53: Molecule of the month. Elesclomol and obatoclax mesylate. Drug News Perspect. 2008 Mar;21(2):123-4. PubMed PMID: 18389103.

54: Bayés M, Rabasseda X. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Jan-Feb;30(1):67-99. PubMed PMID: 18389098.

55: Dong S, Kang S, Lonial S, Khoury HJ, Viallet J, Chen J. Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070. Leukemia. 2008 Mar;22(3):572-7. Epub 2007 Dec 13. PubMed PMID: 18079735; PubMed Central PMCID: PMC2396184.

56: Williamson NR, Fineran PC, Gristwood T, Chawrai SR, Leeper FJ, Salmond GP. Anticancer and immunosuppressive properties of bacterial prodiginines. Future Microbiol. 2007 Dec;2(6):605-18. PubMed PMID: 18041902.

57: Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Bélec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7. Epub 2007 Nov 26. PubMed PMID: 18040043; PubMed Central PMCID: PMC2148320.

58: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jul-Aug;29(6):427-37. PubMed PMID: 17922073.

59: Li J, Viallet J, Haura EB. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol. 2008 Mar;61(3):525-34. Epub 2007 May 16. PubMed PMID: 17505826.

60: Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood. 2007 Jun 15;109(12):5430-8. Epub 2007 Mar 1. PubMed PMID: 17332241.

61: Pérez-Galán P, Roué G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007 May 15;109(10):4441-9. Epub 2007 Jan 16. PubMed PMID: 17227835.

62: Witters LM, Witkoski A, Planas-Silva MD, Berger M, Viallet J, Lipton A. Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor. Oncol Rep. 2007 Feb;17(2):465-9. PubMed PMID: 17203189.

63: Campàs C, Cosialls AM, Barragán M, Iglesias-Serret D, Santidrián AF, Coll-Mulet L, de Frias M, Domingo A, Pons G, Gil J. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol. 2006 Dec;34(12):1663-9. PubMed PMID: 17157163.

64: Shore GC, Viallet J. Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. Hematology Am Soc Hematol Educ Program. 2005:226-30. PubMed PMID: 16304385.