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PDBsum entry 4ccu
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References listed in PDB file
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Key reference
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Title
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Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
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Authors
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Q.Huang,
T.W.Johnson,
S.Bailey,
A.Brooun,
K.D.Bunker,
B.J.Burke,
M.R.Collins,
A.S.Cook,
J.J.Cui,
K.N.Dack,
J.G.Deal,
Y.L.Deng,
D.Dinh,
L.D.Engstrom,
M.He,
J.Hoffman,
R.L.Hoffman,
P.S.Johnson,
R.S.Kania,
H.Lam,
J.L.Lam,
P.T.Le,
Q.Li,
L.Lingardo,
W.Liu,
M.W.Lu,
M.Mctigue,
C.L.Palmer,
P.F.Richardson,
N.W.Sach,
H.Shen,
T.Smeal,
G.L.Smith,
A.E.Stewart,
S.Timofeevski,
K.Tsaparikos,
H.Wang,
H.Zhu,
J.Zhu,
H.Y.Zou,
M.P.Edwards.
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Ref.
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J Med Chem, 2014,
57,
1170-1187.
[DOI no: ]
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PubMed id
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Abstract
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Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase
inhibitor approved by the U.S. Food and Drug Administration in 2011, is
efficacious in ALK and ROS positive patients. Under pressure of crizotinib
treatment, point mutations arise in the kinase domain of ALK, resulting in
resistance and progressive disease. The successful application of both
structure-based and lipophilic-efficiency-focused drug design resulted in
aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant
cell lines and showed suitable preclinical pharmacokinetics and robust tumor
growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
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