6YBJ
Structure of MBP-Mcl-1 in complex with compound 3e
Summary for 6YBJ
| Entry DOI | 10.2210/pdb6ybj/pdb |
| Related | 6YBG 6YBK 6YBL |
| Related PRD ID | PRD_900001 |
| Descriptor | Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | apoptosis, apoptosis-inhibitor complex, mcl-1, s64315, mbp, small molecule inhibitor |
| Biological source | Escherichia coli O157:H7 More |
| Total number of polymer chains | 1 |
| Total formula weight | 58364.88 |
| Authors | Dokurno, P.,Surgenor, A.E.,Murray, J.B. (deposition date: 2020-03-17, release date: 2020-11-18, Last modification date: 2024-01-24) |
| Primary citation | Szlavik, Z.,Csekei, M.,Paczal, A.,Szabo, Z.B.,Sipos, S.,Radics, G.,Proszenyak, A.,Balint, B.,Murray, J.,Davidson, J.,Chen, I.,Dokurno, P.,Surgenor, A.E.,Daniels, Z.M.,Hubbard, R.E.,Le Toumelin-Braizat, G.,Claperon, A.,Lysiak-Auvity, G.,Girard, A.M.,Bruno, A.,Chanrion, M.,Colland, F.,Maragno, A.L.,Demarles, D.,Geneste, O.,Kotschy, A. Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor. J.Med.Chem., 63:13762-13795, 2020 Cited by PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials. PubMed: 33146521DOI: 10.1021/acs.jmedchem.0c01234 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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