5HOA

Crystal structure of c-Met L1195V in complex with SAR125844

5HOA の概要

• エントリーDOI: 10.2210/pdb5hoa/pdb
• 分子名称: Hepatocyte growth factor receptor, 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea (3 entities in total)
• 機能のキーワード: transferase, inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35843.50

構造登録者

Vallee, F.,Marquette, J.-P. (登録日: 2016-01-19, 公開日: 2016-11-23, 最終更新日: 2024-05-08)

主引用文献

Ugolini, A.,Kenigsberg, M.,Rak, A.,Vallee, F.,Houtmann, J.,Lowinski, M.,Capdevila, C.,Khider, J.,Albert, E.,Martinet, N.,Nemecek, C.,Grapinet, S.,Bacque, E.,Roesner, M.,Delaisi, C.,Calvet, L.,Bonche, F.,Semiond, D.,Egile, C.,Goulaouic, H.,Schio, L.
Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).
J.Med.Chem., 59:7066-7074, 2016

PubMed Abstract: The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.

PubMed: 27355974
DOI: 10.1021/acs.jmedchem.6b00280

実験手法

X-RAY DIFFRACTION (2.14 Å)