venetoclax   

GtoPdb Ligand ID: 8318

Synonyms: ABT-199 | GDC-0199 | Venclexta® | Venclyxto®
venetoclax is an approved drug (FDA and EMA (2016))
Compound class: Synthetic organic
Comment: Venetoclax is a BH3 mimetic that selectively targets Bcl-2 [4], utilised for its pro-apoptotic activity. It is noteworthy that venetoclax is the first approved medicine designed to induce a natural process that helps cells self-destruct.
The IUPAC name provided by PubChem matches 'Example 5' claimed in patent US8580794 [1].
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 14
Topological polar surface area 180.41
Molecular weight 867.32
XLogP 9.38
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
Canonical SMILES Clc1ccc(cc1)C1=C(CCC(C1)(C)C)CN1CCN(CC1)c1ccc(c(c1)Oc1cnc2c(c1)cc[nH]2)C(=O)NS(=O)(=O)c1ccc(c(c1)[N+](=O)[O-])NCC1CCOCC1
Isomeric SMILES Clc1ccc(cc1)C1=C(CCC(C1)(C)C)CN1CCN(CC1)c1ccc(c(c1)Oc1cnc2c(c1)cc[nH]2)C(=O)NS(=O)(=O)c1ccc(c(c1)[N+](=O)[O-])NCC1CCOCC1
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)
InChI Key LQBVNQSMGBZMKD-UHFFFAOYSA-N
No information available.
Summary of Clinical Use
Venetoclax (in combination with and in comparison with currently approved anti-neoplastics) was assessed in Phase III clinical trials as a potential treatment for chronic lymphocytic leukemia (CLL). See NCT02005471 and NCT02242942 for full details.
In January 2016, the US FDA granted venetoclax (in combination with hypomethylating agents) breakthrough designation as a first-line treatment for patients with acute myeloid leukemia (AML) who are ineligible to receive high-dose chemotherapy.

Full marketing authorisation: In April 2016, the US FDA granted full approval for venetoclax as an oral treatment regimen for patients with chronic lymphocytic leukemia (CLL) with 17p deletion (or TP53 mutation) (detected by an FDA-approved test), who have received at least one prior therapy. EMA approval followed in December 2016. In June 2018, the FDA expanded approval to include treatment of both CLL and small lymphocytic lymphoma (SLL), with or without 17p deletion in patients who have received at least one prior therapy. This approval is for a combined regimen using venetoclax plus the anti-CD20 monoclonal rituximab [3], and offers a chemotherapy-free option for CLL patients. Venetoclax plus anti-CD20 obinutuzumab gained FDA approval for use in adults with CLL or SLL in May 2019, based on results from the CLL14 trial (NCT02242942).
Mechanism Of Action and Pharmacodynamic Effects
Venetoclax selectively inhibits the ability of the Bcl-2 protein to sequester its pro-apoptotic family members, thereby restoring the apoptotic balance in cells with aberrant Bcl-2 activity. Venetoclax does not inhibit Bcl-xL, so does not exhibit the anti-platelet side-effect of previously investigated non-selective Bcl-2 inhibitors (eg navitoclax; research code ABT-263).
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02005471 A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Phase 3 Interventional Hoffmann-La Roche
NCT02242942 A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax (GDC-0199) Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia Phase 3 Interventional Hoffmann-La Roche
External links