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PDBsum entry 4waf
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Transferase/transferase inhibitor
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PDB id
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4waf
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References listed in PDB file
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Key reference
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Title
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Structure-Based drug design of novel potent and selective tetrahydropyrazolo[1,5-A]pyrazines as atr inhibitors.
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Authors
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P.A.Barsanti,
R.J.Aversa,
X.Jin,
Y.Pan,
Y.Lu,
R.Elling,
R.Jain,
M.Knapp,
J.Lan,
X.Lin,
P.Rudewicz,
J.Sim,
L.Taricani,
G.Thomas,
L.Xiao,
Q.Yue.
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Ref.
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Acs Med Chem Lett, 2015,
6,
37-41.
[DOI no: ]
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PubMed id
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Abstract
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A saturation strategy focused on improving the selectivity and physicochemical
properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and
selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR
crystal structure surrogates was instrumental in providing cocrystal structures
to guide the medicinal chemistry designs. Detailed DMPK studies involving
cyanide and GSH as trapping agents during microsomal incubations, in addition to
deuterium-labeled compounds as mechanistic probes uncovered the molecular basis
for the observed CYP3A4 TDI in the series.
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