1oi9 | pdb_00001oi9
STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR
Structural highlights
Function[CCNA2_HUMAN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity. N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.,Hardcastle IR, Arris CE, Bentley J, Boyle FT, Chen Y, Curtin NJ, Endicott JA, Gibson AE, Golding BT, Griffin RJ, Jewsbury P, Menyerol J, Mesguiche V, Newell DR, Noble ME, Pratt DJ, Wang LZ, Whitfield HJ J Med Chem. 2004 Jul 15;47(15):3710-22. PMID:15239650[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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