Obatoclax

Obatoclax
Names
	IUPAC name 2-(2-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-1H-indole
	Other names GX15-070
Identifiers
CAS Number	803712-67-6 ; 803712-79-0 (mesylate) ;
3D model (JSmol)	Interactive image;
ChemSpider	24539359;
PubChem CID	11404337; 16681698 (mesylate);
UNII	QN4128B52A ; 39200FJ43J (mesylate) ;
	InChI InChI=1S/C20H19N3O/c1-12-8-13(2)21-16(12)10-19-20(24-3)11-18(23-19)17-9-14-6-4-5-7-15(14)22-17/h4-11,21-22H,1-3H3/b19-10+;
	SMILES Cc1cc([nH]c1/C=C/2\C(=CC(=N2)c3cc4ccccc4[nH]3)OC)C;
Properties
Chemical formula	C20H19N3O
Molar mass	317.392 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Obatoclax mesylate, also known as GX15-070, is an experimental drug for the treatment of various types of cancer. It was discovered by Gemin X, which was acquired by Cephalon, which has since been acquired by Teva Pharmaceuticals.^[1] Several Phase II clinical trials were completed that investigated use of obatoclax in the treatment of leukemia, lymphoma, myelofibrosis, and mastocytosis.^[2]^[3]^[4]

Mechanism of action

Obatoclax is an inhibitor of the Bcl-2 family of proteins.^[5] This inhibition induces apoptosis in cancer cells, preventing tumor growth. Solubility has been an issue in the development of the drug.^[6]

Clinical trials

Clinical trial results have been published for treatment of acute myeloid leukemia,^[7] small cell lung cancer,^[8] Hodgkin's lymphoma,^[9] and myelodysplastic syndromes.^[10]

Teva halted a phase III trial in patients with lung cancer before it had begun, citing "business decisions" as the reason.^[11]

References

^ Cephalon Announces Definitive Agreement to Acquire Gemin X, March 21, 2011
^ Parikh, Sameer A.; Kantarjian, Hagop; Schimmer, Aaron; Walsh, William; Asatiani, Ekatherine; El-Shami, Khaled; Winton, Elliott; Verstovsek, Srdan (2010). "Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients with Myelofibrosis". Clinical Lymphoma, Myeloma & Leukemia. 10 (4): 285–9. doi:10.3816/CLML.2010.n.059. PMID 20709666.
^ Gemin X Presents New Data on Obatoclax at the American Society of Hematology Meeting, Dec 9, 2008
^ Obatoclax at ClinicalTrials.gov
^ Konopleva, M.; Watt, J.; Contractor, R.; Tsao, T.; Harris, D.; Estrov, Z.; Bornmann, W.; Kantarjian, H.; Viallet, J.; Samudio, I.; Andreeff, M. (2008). "Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)". Cancer Research. 68 (9): 3413–20. doi:10.1158/0008-5472.CAN-07-1919. PMC 4096127. PMID 18451169.
^ Nguyen, Mai; Cencic, Regina; Ertel, Franziska; Bernier, Cynthia; Pelletier, Jerry; Roulston, Anne; Silvius, John R.; Shore, Gordon C. (2015). "Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim". BMC Cancer. 15: 568. doi:10.1186/s12885-015-1582-5. PMC 4522062. PMID 26231047.
^ Schimmer, Aaron D.; Raza, Azra; Carter, Thomas H.; Claxton, David; Erba, Harry; Deangelo, Daniel J.; Tallman, Martin S.; Goard, Carolyn; Borthakur, Gautam (2014). "A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia". PLOS ONE. 9 (10): e108694. Bibcode:2014PLoSO...9j8694S. doi:10.1371/journal.pone.0108694. PMC 4186779. PMID 25285531.
^ Langer, Corey J.; Albert, Istvan; Ross, Helen J.; Kovacs, Peter; Blakely, L. Johnetta; Pajkos, Gabor; Somfay, Attila; Zatloukal, Petr; Kazarnowicz, Andrzej; Moezi, Mehdi M.; Schreeder, Marshall T.; Schnyder, Judy; Ao-Baslock, Ada; Pathak, Ashutosh K.; Berger, Mark S. (2014). "Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer". Lung Cancer. 85 (3): 420–8. doi:10.1016/j.lungcan.2014.05.003. PMID 24997137.
^ Oki, Y.; Copeland, A.; Hagemeister, F.; Fayad, L. E.; Fanale, M.; Romaguera, J.; Younes, A. (2012). "Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma". Blood. 119 (9): 2171–2. doi:10.1182/blood-2011-11-391037. PMID 22383790.
^ Arellano, Martha L.; Borthakur, Gautam; Berger, Mark; Luer, Jill; Raza, Azra (2014). "A Phase II, Multicenter, Open-Label Study of Obatoclax Mesylate in Patients with Previously Untreated Myelodysplastic Syndromes with Anemia or Thrombocytopenia". Clinical Lymphoma, Myeloma & Leukemia. 14 (6): 534–9. doi:10.1016/j.clml.2014.04.007. PMID 25052051.
^ Clinical trial number NCT01563601 for "Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer" at ClinicalTrials.gov

[1] Cephalon Announces Definitive Agreement to Acquire Gemin X, March 21, 2011

[2] Parikh, Sameer A.; Kantarjian, Hagop; Schimmer, Aaron; Walsh, William; Asatiani, Ekatherine; El-Shami, Khaled; Winton, Elliott; Verstovsek, Srdan (2010). "Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients with Myelofibrosis". Clinical Lymphoma, Myeloma & Leukemia. 10 (4): 285–9. doi:10.3816/CLML.2010.n.059. PMID 20709666.

[3] Gemin X Presents New Data on Obatoclax at the American Society of Hematology Meeting, Dec 9, 2008

[4] Obatoclax at ClinicalTrials.gov

[5] Konopleva, M.; Watt, J.; Contractor, R.; Tsao, T.; Harris, D.; Estrov, Z.; Bornmann, W.; Kantarjian, H.; Viallet, J.; Samudio, I.; Andreeff, M. (2008). "Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)". Cancer Research. 68 (9): 3413–20. doi:10.1158/0008-5472.CAN-07-1919. PMC 4096127. PMID 18451169.

[6] Nguyen, Mai; Cencic, Regina; Ertel, Franziska; Bernier, Cynthia; Pelletier, Jerry; Roulston, Anne; Silvius, John R.; Shore, Gordon C. (2015). "Obatoclax is a direct and potent antagonist of membrane-restricted Mcl-1 and is synthetic lethal with treatment that induces Bim". BMC Cancer. 15: 568. doi:10.1186/s12885-015-1582-5. PMC 4522062. PMID 26231047.

[7] Schimmer, Aaron D.; Raza, Azra; Carter, Thomas H.; Claxton, David; Erba, Harry; Deangelo, Daniel J.; Tallman, Martin S.; Goard, Carolyn; Borthakur, Gautam (2014). "A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia". PLOS ONE. 9 (10): e108694. Bibcode:2014PLoSO...9j8694S. doi:10.1371/journal.pone.0108694. PMC 4186779. PMID 25285531.

[8] Langer, Corey J.; Albert, Istvan; Ross, Helen J.; Kovacs, Peter; Blakely, L. Johnetta; Pajkos, Gabor; Somfay, Attila; Zatloukal, Petr; Kazarnowicz, Andrzej; Moezi, Mehdi M.; Schreeder, Marshall T.; Schnyder, Judy; Ao-Baslock, Ada; Pathak, Ashutosh K.; Berger, Mark S. (2014). "Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer". Lung Cancer. 85 (3): 420–8. doi:10.1016/j.lungcan.2014.05.003. PMID 24997137.

[9] Oki, Y.; Copeland, A.; Hagemeister, F.; Fayad, L. E.; Fanale, M.; Romaguera, J.; Younes, A. (2012). "Experience with obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist in patients with relapsed or refractory classical Hodgkin lymphoma". Blood. 119 (9): 2171–2. doi:10.1182/blood-2011-11-391037. PMID 22383790.

[10] Arellano, Martha L.; Borthakur, Gautam; Berger, Mark; Luer, Jill; Raza, Azra (2014). "A Phase II, Multicenter, Open-Label Study of Obatoclax Mesylate in Patients with Previously Untreated Myelodysplastic Syndromes with Anemia or Thrombocytopenia". Clinical Lymphoma, Myeloma & Leukemia. 14 (6): 534–9. doi:10.1016/j.clml.2014.04.007. PMID 25052051.

[11] Clinical trial number NCT01563601 for "Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer" at ClinicalTrials.gov

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Mechanism of action

Clinical trials

See also

References