1h1q: Difference between revisions

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.

1H1Q is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 2A6 as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: 2AA. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H1Q OCA].  

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