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

Autor: Tron AE; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Belmonte MA; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; LifeMine Therapeutics, Cambridge, MA, USA., Adam A; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; Surface Oncology, Cambridge, MA, USA., Aquila BM; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; Alkermes, Inc., Waltham, MA, USA., Boise LH; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.; Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Chiarparin E; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Cidado J; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Embrey KJ; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Gangl E; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Gibbons FD; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Gregory GP; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3800, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia., Hargreaves D; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Hendricks JA; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Johannes JW; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Johnstone RW; Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.; The Sir Peter MacCallum Center, Department of Oncology, University of Melbourne, Parkville, VIC, 3000, Australia., Kazmirski SL; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; Fulcrum Therapeutics, Cambridge, MA, USA., Kettle JG; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Lamb ML; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Matulis SM; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.; Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Nooka AK; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.; Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Packer MJ; Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, SK10 4TG, UK., Peng B; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Rawlins PB; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Robbins DW; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; Nurix, Inc., San Francisco, CA, USA., Schuller AG; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Su N; Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Yang W; Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Ye Q; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Zheng X; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Secrist JP; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.; LifeMine Therapeutics, Cambridge, MA, USA., Clark EA; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Wilson DM; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK., Fawell SE; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA., Hird AW; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA. alexander.hird@astrazeneca.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Dec 17; Vol. 9 (1), pp. 5341. Date of Electronic Publication: 2018 Dec 17.
DOI: 10.1038/s41467-018-07551-w
Abstrakt: 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).
Databáze: MEDLINE