| Title: |
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia |
| Authors: |
Tron, AE; Belmonte, MA; Adam, A; Aquila, BM; Boise, LH; Chiarparin, E; Cidado, J; Embrey, KJ; Gangl, E; Gibbons, FD; Gregory, GP; Hargreaves, D; Hendricks, JA; Johannes, JW; Johnstone, RW; Kazmirski, SL; Kettle, JG; Lamb, ML; Matulis, SM; Nooka, AK; Packer, MJ; Peng, B; Rawlins, PB; Robbins, DW; Schuller, AG; Su, N; Yang, W; Ye, Q; Zheng, X; Secrist, JP; Clark, EA; Wilson, DM; Fawell, SE; Hird, AW |
| Publisher Information: |
NATURE PUBLISHING GROUP |
| Publication Year: |
2018 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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). |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://hdl.handle.net/11343/253625 |
| Availability: |
https://hdl.handle.net/11343/253625 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.F2E4CD68 |
| Database: |
BASE |