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PDBsum entry 4m3q
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Transferase/transferase inhibitor
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PDB id
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4m3q
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References listed in PDB file
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Key reference
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Title
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Pseudo-Cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new mer kinase inhibitors.
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Authors
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W.Zhang,
D.Zhang,
M.A.Stashko,
D.Deryckere,
D.Hunter,
D.Kireev,
M.J.Miley,
C.Cummings,
M.Lee,
J.Norris-Drouin,
W.M.Stewart,
S.Sather,
Y.Zhou,
G.Kirkpatrick,
M.Machius,
W.P.Janzen,
H.S.Earp,
D.K.Graham,
S.V.Frye,
X.Wang.
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Ref.
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J Med Chem, 2013,
56,
9683-9692.
[DOI no: ]
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PubMed id
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Abstract
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Abnormal activation or overexpression of Mer receptor tyrosine kinase has been
implicated in survival signaling and chemoresistance in many human cancers.
Consequently, Mer is a promising novel cancer therapeutic target. A
structure-based drug design approach using a pseudo-ring replacement strategy
was developed and validated to discover a new family of pyridinepyrimidine
analogues as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was
identified as the lead compound for further investigation based on high
selectivity against other kinases and good pharmacokinetic properties. When
applied to live cells, 10 inhibited steady-state phosphorylation of endogenous
Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a
chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased
colony-forming potential in rhabdoid and NSCLC tumor cells, thereby
demonstrating functional antitumor activity. The results provide a rationale for
further investigation of this compound for therapeutic application in patients
with cancer.
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