Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

• Type of Material: Article
• Authors: Adriana E. Tron, AstraZeneca; Matthew A. Belmonte, AstraZeneca; Ammar Adam, AstraZeneca; Brian M. Aquila, AstraZeneca; Lawrence Boise, Emory University; Elisabetta Chiarparin, AstraZeneca; Justin Cidado, AstraZeneca; Kevin J. Embrey, AstraZeneca; Eric Gangl, AstraZeneca; Francis D. Gibbons, AstraZeneca; Gareth P. Gregory, Monash University; David Hargreaves, AstraZeneca; J. Adam Hendricks, AstraZeneca; Jeffrey W. Johannes, AstraZeneca; Ricky W. Johnstone, Peter MacCallum Cancer Center; Steven L. Kazmirski, Fulcrum Therapeutics; Jason G. Kettle, AstraZeneca; Michelle L. Lamb, AstraZeneca; Shannon Matulis, Emory University; Ajay Nooka, Emory University; Martin J. Packer, Emory University; Bo Peng, AstraZeneca; Philip B. Rawlins, AstraZeneca; Daniel W. Robbins, AstraZeneca; Alwin G. Schuller, AstraZeneca; Nancy Su, AstraZeneca; Wenzhan Yang, AstraZeneca; Qing Ye, AstraZeneca; Xiaolan Zheng, AstraZeneca; J. Paul Secrist, AstraZeneca; Edwin A. Clark, AstraZeneca; David M. Wilson, AstraZeneca; Stephen E. Fawell, AstraZeneca; Alexander W. Hird, AstraZeneca
• Language: English
• Date: 2018-12-17
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-07551-w
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 5341
• End Page: 5341
• Keywords: ABT-199; Science & Technology; APOPTOSIS; Multidisciplinary Sciences; SURVIVAL; MCL-1 INHIBITORS; BIM; B-CELL LYMPHOMA; TARGET; RESISTANCE; BCL2; VENETOCLAX; Science & Technology - Other Topics
• Research Categories: Health Sciences, Rehabilitation and Therapy; Health Sciences, Oncology

Abstract

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).