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PDBsum entry 4agw
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PDB id:
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Transferase
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Title:
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Discovery of a small molecule type ii inhibitor of wild-type and gatekeeper mutants of bcr-abl, pdgfralpha, kit, and src kinases
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Structure:
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Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: kinase domain, residues 251-533. Synonym: src kinase, proto-oncogenE C-src, pp60c-src, p60-src. Engineered: yes
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Source:
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Gallus gallus. Organism_taxid: 9031. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.60Å
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R-factor:
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0.230
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R-free:
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0.271
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Authors:
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E.Weisberg,H.G.Choi,M.Seeliger,N.Gray,J.D.Griffin
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Key ref:
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E.Weisberg
et al.
(2010).
Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
Blood,
115,
4206-4216.
PubMed id:
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Date:
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01-Feb-12
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Release date:
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15-Feb-12
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PROCHECK
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Headers
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References
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P00523
(SRC_CHICK) -
Proto-oncogene tyrosine-protein kinase Src from Gallus gallus
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Seq:
Struc:
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533 a.a.
258 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Blood
115:4206-4216
(2010)
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PubMed id:
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Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.
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E.Weisberg,
H.G.Choi,
A.Ray,
R.Barrett,
J.Zhang,
T.Sim,
W.Zhou,
M.Seeliger,
M.Cameron,
M.Azam,
J.A.Fletcher,
M.Debiec-Rychter,
M.Mayeda,
D.Moreno,
A.L.Kung,
P.A.Janne,
R.Khosravi-Far,
J.V.Melo,
P.W.Manley,
S.Adamia,
C.Wu,
N.Gray,
J.D.Griffin.
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ABSTRACT
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Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR,
become resistant to adenosine triphosphate-competitive inhibitors through
mutation of the so-called gatekeeper amino acid from a threonine to a large
hydrophobic amino acid, such as an isoleucine or methionine. We have developed a
new class of adenosine triphosphate competitive inhibitors, exemplified by
HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed
in chronic myeloid leukemia), T670I-c-Kit (clinically observed in
gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in
hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported
kinase inhibitors in having the ability to accommodate either a gatekeeper
threonine, present in the wild-type forms of these kinases, or a large
hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The
distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and
mutant forms of several kinases of clinical relevance is an important step in
the development of the next generation of tyrosine kinase inhibitors.
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