1h1r
STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH THE INHIBITOR NU6086
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OverviewOverview
Aberrant control of cyclin-dependent kinases (CDKs) is a central feature, of the molecular pathology of cancer. Iterative structure-based design was, used to optimize the ATP- competitive inhibition of CDK1 and CDK2 by, O(6)-cyclohexylmethylguanines, resulting in O(6)-cyclohexylmethyl-2-(4'-, sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than, the parent compound (K(i) values for CDK1 = 9 nM and CDK2 = 6 nM versus, 5,000 nM and 12,000 nM, respectively, for O(6)-cyclohexylmethylguanine)., The increased potency arises primarily from the formation of two, additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which, facilitate optimum hydrophobic packing of the anilino group with the, specificity surface of CDK2. Cellular studies with, O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino) purine demonstrated, inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first, successful iterative synthesis of a potent CDK inhibitor based on the, structure of fully activated CDK2-cyclin A. Furthermore, the potency of, O(6)-cyclohexylmethyl-2-(4'- sulfamoylanilino)purine was both predicted, and fully rationalized on the basis of protein-ligand interactions.
About this StructureAbout this Structure
1H1R is a Protein complex structure of sequences from Homo sapiens with 6CP as ligand. Structure known Active Site: CPA. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor., Davies TG, Bentley J, Arris CE, Boyle FT, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Hardcastle IR, Jewsbury P, Johnson LN, Mesguiche V, Newell DR, Noble ME, Tucker JA, Wang L, Whitfield HJ, Nat Struct Biol. 2002 Oct;9(10):745-9. PMID:12244298
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