 |
PDBsum entry 5fxq
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Igfr-1r complex with a pyrimidine inhibitor.
|
|
Structure:
|
|
Insulin-like growth factor 1 receptor. Chain: a. Fragment: kinase, unp residues 980-1286. Synonym: insulin-like growth factor i receptor, igf-i receptor, igfr- 1r. Engineered: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
2.30Å
|
R-factor:
|
not given
|
R-free:
|
0.275
|
|
|
Authors:
|
|
S.Degorce,S.Boyd,J.Curwen,R.Ducray,C.Halsall,C.Jones,F.Lach,E.Lenz, M.Pass,S.Pass,C.Trigwell,R.Norman,C.Phillips
|
|
Key ref:
|
|
S.L.Degorce
et al.
(2016).
Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R).
J Med Chem,
59,
4859-4866.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
02-Mar-16
|
Release date:
|
19-Oct-16
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P08069
(IGF1R_HUMAN) -
Insulin-like growth factor 1 receptor from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1367 a.a.
302 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
59:4859-4866
(2016)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R).
|
|
S.L.Degorce,
S.Boyd,
J.O.Curwen,
R.Ducray,
C.T.Halsall,
C.D.Jones,
F.Lach,
E.M.Lenz,
M.Pass,
S.Pass,
C.Trigwell.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Optimization of cellular lipophilic ligand efficiency (LLE) in a series of
2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel
2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties.
Replacement of the imidazo[1,2-a]pyridine group of the previously reported
inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular
potency. Substitution of the amino-pyrazole group was key to obtaining excellent
kinase selectivity and pharmacokinetic parameters suitable for oral dosing,
which led to the discovery of
(2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone
(AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
