8OWG

Crystal structure of D1228V c-MET bound by compound 2

8OWG の概要

• エントリーDOI: 10.2210/pdb8owg/pdb
• 分子名称: Hepatocyte growth factor receptor, 5-[3,5-bis(fluoranyl)phenyl]-1-[(1S)-1-phenylethyl]pyrimidine-2,4-dione (3 entities in total)
• 機能のキーワード: kinase, inhibitor, cancer research, drug discovery, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 105464.03

構造登録者

Collie, G.W. (登録日: 2023-04-27, 公開日: 2023-07-05, 最終更新日: 2024-06-19)

主引用文献

Michaelides, I.N.,Collie, G.W.,Borjesson, U.,Vasalou, C.,Alkhatib, O.,Barlind, L.,Cheung, T.,Dale, I.L.,Embrey, K.J.,Hennessy, E.J.,Khurana, P.,Koh, C.M.,Lamb, M.L.,Liu, J.,Moss, T.A.,O'Neill, D.J.,Phillips, C.,Shaw, J.,Snijder, A.,Storer, R.I.,Stubbs, C.J.,Han, F.,Li, C.,Qiao, J.,Sun, D.Q.,Wang, J.,Wang, P.,Yang, W.
Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor.
J.Med.Chem., 66:8782-8807, 2023

PubMed Abstract: Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.

PubMed: 37343272
DOI: 10.1021/acs.jmedchem.3c00401

実験手法

X-RAY DIFFRACTION (2.631 Å)