5HOA

Crystal structure of c-Met L1195V in complex with SAR125844

Summary for 5HOA

• Entry DOI: 10.2210/pdb5hoa/pdb
• Descriptor: 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)
• Functional Keywords: transferase, inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 35843.50

Authors

Vallee, F.,Marquette, J.-P. (deposition date: 2016-01-19, release date: 2016-11-23, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.14 Å)