Data from AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-x&lt;sub&gt;L&lt;/sub&gt;, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia

Ammar Adam,Patricia Jaaks,J Paul Secrist,Jeffrey W Tyner,Stephanos Ioannidis,Areya Tabatabai,Tristan Lubinski,Eric Gangl,Michael Zinda,Gareth P Gregory,William Mccoull,Stephen E Kurtz,Andrea Newbold,Martin Wild,Steven W Criscione,Shenghua Wen,Francis D Gibbons,Omid Tavana,Jamal C Saeh,Justin Cidado,Srividya B Balachander,Elizabeth A Coker,Barry R Davies,Shannon K Mcweeney,Stephen E Fawell,Terry Macintyre,Paula Lewis,Mathew J Garnett,R Bruce Diebold,Ricky W Johnstone,Nancy Su,Deborah Lawson,Jeffrey Varnes,Edward J Hennessy,Alwin G Schuller ,Kathleen A Burke ,Thomas W Gero ,Kate F Byth

doi:10.1158/1078-0432.c.6529392.v1

Abstract

<div>AbstractPurpose: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/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.Results:We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.Conclusions:AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.</div>

Full Text