6YBK

Structure of MBP-Mcl-1 in complex with compound 4d

6YBK の概要

• エントリーDOI: 10.2210/pdb6ybk/pdb
• 関連するPDBエントリー: 6YBG 6YBJ 6YBL
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: 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)
• 機能のキーワード: apoptosis, apoptosis-inhibitor complex, mcl-1, s64315, mbp, small molecule inhibitor
• 由来する生物種: Escherichia coli O157:H7; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58372.90

構造登録者

Dokurno, P.,Surgenor, A.E.,Murray, J.B. (登録日: 2020-03-17, 公開日: 2020-11-18, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)