作者
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, Alexander W Hird
发表日期
2018/12/17
期刊
Nature communications
卷号
9
期号
1
页码范围
5341
出版商
Nature Publishing Group UK
简介
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 …
学术搜索中的文章
AE Tron, MA Belmonte, A Adam, BM Aquila, LH Boise… - Nature communications, 2018