6FS0
INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH AZD5991
Summary for 6FS0
| Entry DOI | 10.2210/pdb6fs0/pdb |
| Related | 5MES |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, Fab Heavy Chain, Fab Light Chain, ... (5 entities in total) |
| Functional Keywords | mcl1-fab4460.55, apoptosis |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 64502.70 |
| Authors | Hargreaves, D. (deposition date: 2018-02-18, release date: 2018-12-26, Last modification date: 2024-10-16) |
| Primary citation | 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.,Nooka, A.K.,Packer, M.J.,Peng, B.,Rawlins, P.B.,Robbins, D.W.,Schuller, A.G.,Su, N.,Yang, W.,Ye, Q.,Zheng, X.,Secrist, J.P.,Clark, E.A.,Wilson, D.M.,Fawell, S.E.,Hird, A.W. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun, 9:5341-5341, 2018 Cited by PubMed 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 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). PubMed: 30559424DOI: 10.1038/s41467-018-07551-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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