Selective Mcl-1 Inhibition by AZD5991 Induces On-Target Cell Death and Achieves Antitumor Activity in Multiple Myeloma and Acute Myeloid Leukemia

Abstract Mcl-1 is a member of the Bcl/Mcl family of proteins that promotes cell survival by preventing induction of apoptosis in a broad range of cancers. High expression of Mcl-1 has been linked to tumor development and resistance to anticancer therapies, underscoring the potential of Mcl-1 inhibitors as anticancer drugs. We have previously shown that AZD5991, a rationally designed macrocycle with sub-nanomolar affinity for Mcl-1 and high selectivity, induces rapid and irreversible commitment to apoptosis in Mcl-1-dependent cancer cells in a manner dependent on proapoptotic BAK. Here, we demonstrate that AZD5991 exhibits cytotoxic activity (GI50<100nM) in various MM and AML cell lines in vitro with an activity profile distinct from the selective Bcl2 inhibitor venetoclax. In vivo, AZD5991 shows potent antitumor activity with complete (100%) tumor regression in several mouse MM and AML xenograft models after a single tolerated dose. AZD5991 shows enhanced efficacy in vivo when combined with standard-of-care agents. Pharmacodynamic studies confirmed that AZD5991 kills cancer cells by activation of the mitochondrial apoptotic pathway. Ex vivo analysis indicates that AZD5991 has single agent activity in primary AML patient samples with LC50 values in the low nanomolar range. Consistent with our findings in AML cell lines, the activity profile for AZD5991 in AML primary samples was distinct from venetoclax, highlighting the unique therapeutic opportunity for AZD5991. Based on these data a phase I clinical trial has been launched for evaluation of AZD5991 in patients with MM and other hematologic malignancies (NCT03218683). Citation Format: Adriana E. Tron, Matthew A. Belmonte, Steven Criscione, Edwin A. Clark, Eric Gangl, Francis D. Gibbons, Jeffrey W. Tyner, Stephen E. Kurtz, Qing Ye, Alexander W. Hird, Alwin Schuller, J. Paul Secrist. Selective Mcl-1 inhibition by AZD5991 induces on-target cell death and achieves antitumor activity in multiple myeloma and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 302.