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

Adriana E. Tron, Matthew A. Belmonte, Ammar Adam, Brian M. Aquila, Lawrence H. Boise, Elisabetta Chiarparin, Justin Cidado, Kevin J. Embrey, Eric Gangl, Francis D. Gibbons, Gareth P. Gregory, David Hargreaves, J. Adam Hendricks, Jeffrey W. Johannes, Ricky W. Johnstone, Steven L. Kazmirski, Jason G. Kettle, Michelle L. Lamb, Shannon M. Matulis, Ajay K. Nooka, Martin J. Packer, Bo Peng, Philip B. Rawlins, Daniel W. Robbins, Alwin G. Schuller, Nancy Su, Wenzhan Yang, Qing Ye, Xiaolan Zheng, J. Paul Secrist, Edwin A. Clark, David M. Wilson, Stephen E. Fawell and Alexander W. Hird ()
Additional contact information
Adriana E. Tron: AstraZeneca
Matthew A. Belmonte: AstraZeneca
Ammar Adam: AstraZeneca
Brian M. Aquila: AstraZeneca
Lawrence H. Boise: Emory University School of Medicine
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 Centre
Steven L. Kazmirski: AstraZeneca
Jason G. Kettle: AstraZeneca
Michelle L. Lamb: AstraZeneca
Shannon M. Matulis: Emory University School of Medicine
Ajay K. Nooka: Emory University School of Medicine
Martin J. Packer: AstraZeneca
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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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).

Date: 2018
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DOI: 10.1038/s41467-018-07551-w

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