Srividya B Balachander, Steven W Criscione, Kate F Byth, Justin Cidado, Ammar Adam, Paula Lewis, Terry Macintyre, Shenghua Wen, Deborah Lawson, Kathleen Burke, Tristan Lubinski, Jeffrey W Tyner, Stephen E Kurtz, Shannon K McWeeney, Jeffrey Varnes, R Bruce Diebold, Thomas Gero, Stephanos Ioannidis, Edward J Hennessy, William McCoull, Jamal C Saeh, Areya Tabatabai, Omid Tavana, Nancy Su, Alwin Schuller, Mathew J Garnett, Patricia Jaaks, Elizabeth A Coker, Gareth P Gregory, Andrea Newbold, Ricky W Johnstone, Eric Gangl, Martin Wild, Michael Zinda, J Paul Secrist, Barry R Davies, Stephen E Fawell, Francis D Gibbons
PURPOSE: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-xL , has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL -mediated thrombocytopenia. EXPERIMENTAL DESIGN: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models...
December 15, 2020: Clinical Cancer Research