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

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Tron, AE; Belmonte, MA; Adam, A; Aquila, BM; Boise, LH; Chiarparin, E; Cidado, J; Embrey, KJ; Gangl, E; Gibbons, FD; ...Date
2018-12-17Source Title
Nature CommunicationsPublisher
NATURE PUBLISHING GROUPAffiliation
Sir Peter MacCallum Department of OncologyUniversity General
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Tron, A. E., Belmonte, M. A., Adam, A., Aquila, B. M., Boise, L. H., Chiarparin, E., Cidado, J., Embrey, K. J., Gangl, E., Gibbons, F. D., Gregory, G. P., Hargreaves, D., Hendricks, J. A., Johannes, J. W., Johnstone, R. W., Kazmirski, S. L., Kettle, J. G., Lamb, M. L., Matulis, S. M. ,... Hird, A. W. (2018). Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-07551-w.Access Status
Open AccessAbstract
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).
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