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'''STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR''' | '''STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR''' | ||
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[[Category: Noble, M E.M.]] | [[Category: Noble, M E.M.]] | ||
[[Category: Pratt, D J.]] | [[Category: Pratt, D J.]] | ||
[[Category: | [[Category: Atp-binding]] | ||
[[Category: | [[Category: Cell cycle]] | ||
[[Category: | [[Category: Cell division]] | ||
[[Category: | [[Category: Kinase]] | ||
[[Category: | [[Category: Mitosis]] | ||
[[Category: | [[Category: Phosphorylation]] | ||
[[Category: | [[Category: Serine/threonine-protein kinase]] | ||
[[Category: | [[Category: Transferase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 03:52:47 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 03:52, 3 May 2008
STRUCTURE OF HUMAN THR160-PHOSPHO CDK2/CYCLIN A COMPLEXED WITH A 6-CYCLOHEXYLMETHYLOXY-2-ANILINO-PURINE INHIBITOR
OverviewOverview
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.
About this StructureAbout this Structure
1OI9 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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 Page seeded by OCA on Sat May 3 03:52:47 2008