4R1Y

Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitor

Summary for 4R1Y

• Entry DOI: 10.2210/pdb4r1y/pdb
• Related: 4R1V
• Descriptor: Hepatocyte growth factor receptor, 3-(diethylamino)propyl (3-{[5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]methyl}phenyl)carbamate, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (4 entities in total)
• Functional Keywords: transferase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/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: 34183.83

Authors

Blaukat, A.,Bladt, F.,Friese-Hamim, M.,Knuehl, C.,Fittschen, C.,Graedler, U.,Meyring, M.,Dorsch, D.,Stieber, F.,Schadt, O. (deposition date: 2014-08-08, release date: 2015-03-18, Last modification date: 2024-02-28)

Primary citation

Dorsch, D.,Schadt, O.,Stieber, F.,Meyring, M.,Gradler, U.,Bladt, F.,Friese-Hamim, M.,Knuhl, C.,Pehl, U.,Blaukat, A.
Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.
Bioorg.Med.Chem.Lett., 25:1597-1602, 2015

PubMed Abstract: In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.

PubMed: 25736998
DOI: 10.1016/j.bmcl.2015.02.002

Experimental method

X-RAY DIFFRACTION (2 Å)