PDBsum entry 4r1v

Transferase/transferase inhibitor

PDB id: 4r1v

Contents

Protein chain

289 a.a.

Ligands

3E8

GBL ×3

Waters ×349

PDB id:

4r1v

Name:

Transferase/transferase inhibitor

Title:

Identification and optimization of pyridazinones as potent and selectivE C-met kinase inhibitors

Structure:

Hepatocyte growth factor receptor. Chain: a. Fragment: kinase domain, unp residues 1055-1345. Synonym: hgf receptor, hgf/sf receptor, proto-oncogenE C-met, scatter factor receptor, sf receptor, tyrosine-protein kinase met. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: met. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.20Å R-factor: 0.146 R-free: 0.176

Authors:

A.Blaukat,F.Bladt,M.Friese-Hamim,C.Knuehl,C.Fittschen,U.Graedler, M.Meyring,D.Dorsch,F.Stieber,O.Schadt

Key ref:

D.Dorsch et al. (2015). Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors. Bioorg Med Chem Lett, 25, 1597-1602. PubMed id: 25736998 DOI: 10.1016/j.bmcl.2015.02.002

Date:

07-Aug-14 Release date: 18-Mar-15

Protein chain

P08581  (MET_HUMAN) -  Hepatocyte growth factor receptor from Homo sapiens

Seq: 1390 a.a.

Struc: 289 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2015.02.002

Bioorg Med Chem Lett 25:1597-1602 (2015)

PubMed id: 25736998

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

D.Dorsch, O.Schadt, F.Stieber, M.Meyring, U.Grädler, F.Bladt, M.Friese-Hamim, C.Knühl, U.Pehl, A.Blaukat.

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.