1oi9: Difference between revisions

The 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.

1OI9 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 MG, N20 and SGM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OI9 OCA].  

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