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Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w.

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

Author information

1
Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
2
LifeMine Therapeutics, Cambridge, MA, USA.
3
Surface Oncology, Cambridge, MA, USA.
4
Alkermes, Inc., Waltham, MA, USA.
5
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
6
Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
7
Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
8
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
9
School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3800, Australia.
10
Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
11
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
12
The Sir Peter MacCallum Center, Department of Oncology, University of Melbourne, Parkville, VIC, 3000, Australia.
13
Fulcrum Therapeutics, Cambridge, MA, USA.
14
Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, SK10 4TG, UK.
15
Nurix, Inc., San Francisco, CA, USA.
16
Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
17
Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA. alexander.hird@astrazeneca.com.

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).

PMID:
30559424
PMCID:
PMC6297231
DOI:
10.1038/s41467-018-07551-w
[Indexed for MEDLINE]
Free PMC Article

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