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PDBsum entry 3qqk
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Transferase/transferase inhibitor
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PDB id
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3qqk
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References listed in PDB file
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Key reference
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Title
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Development of highly potent and selective diaminothiazole inhibitors of cyclin-Dependent kinases.
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Authors
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E.Schonbrunn,
S.Betzi,
R.Alam,
M.P.Martin,
A.Becker,
H.Han,
R.Francis,
R.Chakrasali,
S.Jakkaraj,
A.Kazi,
S.M.Sebti,
C.L.Cubitt,
A.W.Gebhard,
L.A.Hazlehurst,
J.S.Tash,
G.I.Georg.
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Ref.
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J Med Chem, 2013,
56,
3768-3782.
[DOI no: ]
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PubMed id
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Abstract
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Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as
key regulatory elements in cell cycle progression. We describe the development
of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM)
from a single hit compound with weak inhibitory activity (IC50 = 15 μM),
discovered by high-throughput screening. Structure-based design was performed
using 35 cocrystal structures of CDK2 liganded with distinct analogues of the
parent compound. The profiling of compound 51 against a panel of 339 kinases
revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9,
CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15
cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated
with the complete suppression of retinoblastoma phosphorylation and the onset of
apoptosis. Combined, the results demonstrate the potential of this new
inhibitors series for further development into CDK-specific chemical probes or
therapeutics.
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