AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-x(L), Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia
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 Show all
Clinical Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2020
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. We applied pharmacokinetic/pharmacodynam..View full abstract
Awarded by Wellcome Trust
We acknowledge the support of Prasad Nadella for reading IHC slides, Galina Repik and Cheryl Campbell for generating data, Kelly Theriault for generating constructs, Meghan Scarpitti for retroviral support, Erin Code and Xiahui Zhu for preparing purified Bcl-2 family proteins for the FP assays, Clare Hoover for reading the platelet data, and Patrick Brassil for DMPK support. The Sanger panel screen was supported by the Wellcome Trust grant 206194 (to M.J. Garnett). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.