The New Drugs on the Horizon session at the recent annual American Association for Cancer Research (AACR) meeting in Chicago showcased several drugs that I expect we will be hearing more of in the future. I previously wrote about AZD3514 in prostate cancer.
Another small molecule that particularly impressed me in this AACR session was ABT-199, a potent and selective inhibitor of Bcl-2. Steven Elmore from Abbott Laboratories presented impressive early data from an ongoing phase I trial in patients with chronic lymphocytic leukemia (CLL).
Bcl-2 is part of the signaling pathway for apoptosis Image Source: WikiCommons Author: Cybertory
The Bcl-2 (B-cell lymphoma 2) gene has a potential involvement in many cancers including melanoma, breast cancer, CLL and lung cancer.
As an example, Sally Church, PhD on Pharma Strategy Blog has written about how the Bcl-2 family protein Mcl-1 is involved BRAF resistance, and how RNA silencing of Mcl-1 enhances ABT-737 mediated apoptosis in melanoma.
Inhibition of Bcl-2 presents a particularly promising target in CLL
Anthony Letai (Dana-Farber Cancer Institute) wrote in “Blood” last year, “antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies.” (doi: 10.1182/blood-2011-08-370346)
The Bcl-2 family of proteins regulates the programmed cell death (apoptosis) that takes place in the mitochondrion. One way that cancer cells can survive is by disrupting the apoptosis signaling pathway, and thereby avoiding cell death.
Proteins that prevent apotosis (anti-anti-apoptotic proteins) include Bcl-2, Bcl-xl, Mcl-1. Targeting Bcl-2 can therefore induce apoptosis or cell death, and has been shown to be a successful strategy to kill leukemia and lymphoma cells.
For those interested in more information, the 2009 article (full text free) by Josyln Brunelle and Anthony Letai published in the Journal of Cell Science offers considerable insight into the Control of mitochondrial apopotosis by the Bcl-2 family” (doi 10.1242/ jcs.031682).
ABT-199 is a potent & selective Bcl-2 inhibitor
Abbott & Genetech have previously targeted Bcl-2 and Bcl-xl with navitoclax (ABT-263), currently in clinical trials for CLL & NHL.
As Steven Elmore of Abbott mentioned in his AACR presentation, the problem with navitoclax is that circulating platelet survival is dependent on Bcl-xl. When you inhibit Bcl-xl you end up with dose-dependent thrombocytopenia in patients. This has been a dose-limiting side effect with navitoclax.
So the goal in the development of ABT-199 was to inhibit Bcl-2, which is critical for the survival of cancer cells & avoidance of apoptosis, while at the same time not inhibiting Bcl-xl which is critical for the survival of circulating platelets.
ABT-199 is a reverse engineered version of ABT-263, that has a high affinity for Bcl-2 and lower affinity for Bcl-xl.
I captured some of the AACR live-tweets about ABT-199 in the Storify below (if you can’t see the embedded information, click here to read this on Storify).
ABT-199 is an exciting new Bcl-2 inhibitor with a solid scientific rationale for success in CLL and promising initial data. From what I saw at AACR, it is definitely a compound to watch.
According to Steven Elmore, full results from the Phase 1 CLL trial with ABT-199 will be presented at the 2012 European Hematology Association (EHA) Congress held in Amsterdam from June 14 -17.