Journal article
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
AE Tron, MA Belmonte, A Adam, BM Aquila, LH Boise, E Chiarparin, J Cidado, KJ Embrey, E Gangl, FD Gibbons, GP Gregory, D Hargreaves, JA Hendricks, JW Johannes, RW Johnstone, SL Kazmirski, JG Kettle, ML Lamb, SM Matulis, AK Nooka Show all
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
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 vi..
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