BCl-2 Inhibitor, ABT-199

• CAT Number: I001028
• CAS Number: 1257044-40-8
• Molecular Formula: C₄₅H₅₀ClN₇O₇S
• Molecular Weight: 868.44
• Purity: ≥95%
• Target: Bcl-2 Family
• Solubility: DMSO: ≥ 51 mg/mL
• Storage: 0°C (short term), -20°C (long term), desiccated
• IC50: <0.01 nM (Ki)
• IUPAC Name: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
• InChI: InChI=1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)
• InChIKey: LQBVNQSMGBZMKD-UHFFFAOYSA-N
• SMILES: CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C

ABT-199 (CAS 1257044-40-8), also known as GDC-0199, is a Bcl-2-selective inhibitor with Ki of 0.01 nM, 4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-1. ABT-199 inhibits the growth of Bcl-2-dependent cell lines and in vivo tumor xenografts. This compound has shown antileukemic activity in patients with refractory chronic lymphocytic leukemia and holds promise to address additional Bcl-2-dependent cancers.

Overview of Clinical Research

Originator: Abbott Laboratories; Genentech; Walter and Eliza Hall Institute of Medical Research
Developer: AbbVie; Dana-Farber Cancer Institute; Genentech; Janssen Research & Development; Nantes University Hospital; Pharmacyclics; Roche
Class: Antineoplastics; Benzamides; Heterocyclic bicyclo compounds; Piperazines; Pyrans; Pyridines; Pyrroles; Small molecules; Sulfonamides
Mechanism of Action: Apoptosis stimulants; Proto-oncogene protein c-bcl-2 inhibitors
Orphan Drug Status: Yes – Diffuse large B cell lymphoma; Acute myeloid leukaemia; Chronic lymphocytic leukaemia; Multiple myeloma

Reference

1. Ther Adv Hematol. 2016 Oct;7(5):270-287. Epub 2016 Jul 8.
The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia.
Itchaki G(1), Brown JR(2).
Author information:
(1)Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel. (2)Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN. We further strive to contextualize VEN in the current CLL treatment landscape and discuss potential mechanisms of resistance.
2. J Hematol Oncol. 2015 Nov 20;8:129. doi: 10.1186/s13045-015-0224-3.
ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development.
Cang S(1), Iragavarapu C(2), Savooji J(2), Song Y(3), Liu D(4).
Author information:
(1)Department of Oncology, The Henan Province People/'s Hospital, Zhengzhou, China. (2)Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, New York, 10595, USA. (3)Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. (4)Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. .
With the advent of new agents targeting CD20, Bruton/'s tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.