1OIU

Structure of human Thr160-phospho CDK2/cyclin A complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor

Summary for 1OIU

• Entry DOI: 10.2210/pdb1oiu/pdb
• Related: 1AQ1 1B38 1B39 1BUH 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1F5Q 1FIN 1FQ1 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GY3 1GZ8 1H00 1H01 1H06 1H07 1H08 1H0U 1H0V 1H0W 1H1P 1H1Q 1H1R 1H1S 1H24 1H25 1H26 1H27 1H28 1HCK 1HCL 1JST 1JSU 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1OGU 1QMZ
• Descriptor: CELL DIVISION PROTEIN KINASE 2, CYCLIN A2, 3-(6-CYCLOHEXYLMETHOXY-9H-PURIN-2-YLAMINO)-BENZENESULFONAMIDE, ... (6 entities in total)
• Functional Keywords: kinase, transferase, serine/threonine-protein kinase, atp-binding, cell cycle, cell division, mitosis, phosphorylation
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus: 1OIU
• Total number of polymer chains: 4
• Total formula weight: 129524.31

Authors

Pratt, D.J.,Endicott, J.A.,Noble, M.E.M. (deposition date: 2003-06-26, release date: 2004-07-13, Last modification date: 2024-11-06)

Primary citation

Hardcastle, I.R.,Arris, C.E.,Bentley, J.,Boyle, F.T.,Chen, Y.,Curtin, N.J.,Endicott, J.A.,Gibson, A.E.,Golding, B.T.,Griffin, R.J.,Jewsbury, P.,Menyerol, J.,Mesguiche, V.,Newell, D.R.,Noble, M.E.M.,Pratt, D.J.,Wang, L.-Z.,Whitfield, H.J.
N2-Substituted O6-Cyclohexylmethylguanine Derivatives: Potent Inhibitors of Cyclin-Dependent Kinases 1 and 2
J.Med.Chem., 47:3710-, 2004

PubMed Abstract: 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.

PubMed: 15239650
DOI: 10.1021/JM0311442

Experimental method

X-RAY DIFFRACTION (2 Å)