6YBL

Structure of MBP-Mcl-1 in complex with compound 9m

Summary for 6YBL

• Entry DOI: 10.2210/pdb6ybl/pdb
• Related: 6YBG 6YBJ 6YBK
• 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, (2~{R})-2-[5-[3-chloranyl-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid, ... (4 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: 58443.57

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

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: 33146521
DOI: 10.1021/acs.jmedchem.0c01234

Experimental method

X-RAY DIFFRACTION (2.1 Å)