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PDBsum entry 4bch
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Transferase/cell cycle
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PDB id
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4bch
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References listed in PDB file
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Key reference
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Title
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Comparative structural and functional studies of 4-(Thiazol-5-Yl)-2-(Phenylamino)pyrimidine-5-Carbonitrile cdk9 inhibitors suggest the basis for isotype selectivity.
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Authors
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A.J.Hole,
S.Baumli,
H.Shao,
S.Shi,
S.Huang,
C.Pepper,
P.M.Fischer,
S.Wang,
J.A.Endicott,
M.E.Noble.
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Ref.
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J Med Chem, 2013,
56,
660-670.
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PubMed id
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Abstract
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Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that
constitutes positive transcription elongation factor b, is a well-validated
target for treatment of several diseases, including cancer and cardiac
hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9
selectivity, we have studied the CDK-binding properties of six different members
of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind
to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the
melting temperature of a CDK/cyclin/inhibitor complex correlates well with
inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a
useful orthogonal measure of inhibitory activity for this series. We have used
DSF to demonstrate that the binding of these compounds is independent of the
presence or absence of the C-terminal tail region of CDK9, unlike the binding of
the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside
(DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T
or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by
members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series
results from the relative malleability of the CDK9 active site rather than from
the formation of specific polar contacts.
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