 |
PDBsum entry 5ho6
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Crystal structure of cmet in complex with cmpd.
|
|
Structure:
|
|
Hepatocyte growth factor receptor. Chain: a. Synonym: hgf receptor,hgf/sf receptor,proto-oncogenE C-met,scatter factor receptor,sf receptor,tyrosine-protein kinase met. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: met. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
1.97Å
|
R-factor:
|
not given
|
|
|
Authors:
|
|
F.Vallee,J.Houtmann
|
|
Key ref:
|
|
A.Ugolini
et al.
(2016).
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.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
19-Jan-16
|
Release date:
|
23-Nov-16
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P08581
(MET_HUMAN) -
Hepatocyte growth factor receptor from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1390 a.a.
240 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
|
|
|
|
|
|
|
Reaction:
|
|
L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
|
|
|
|
|
|
L-tyrosyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-tyrosyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
59:7066-7074
(2016)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
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).
|
|
A.Ugolini,
M.Kenigsberg,
A.Rak,
F.Vallée,
J.Houtmann,
M.Lowinski,
C.Capdevila,
J.Khider,
E.Albert,
N.Martinet,
C.Nemecek,
S.Grapinet,
E.Bacqué,
M.Roesner,
C.Delaisi,
L.Calvet,
F.Bonche,
D.Semiond,
C.Egile,
H.Goulaouic,
L.Schio.
|
|
|
|
|
| |
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.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
