N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.

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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

N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.

J Med Chem. 2004 Jul 15;47(15):3710-22.

PubMed ID

15239650 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-(6-CYCLOHEXYLMETHOXY-9H-PURIN-2-YLAMINO)-BENZENESULFONAMIDE	Cyclin-dependent kinase 2	IC 50 (nM)	210	7.5	30	Details
4-(6-CYCLOHEXYLMETHOXY-9H-PURIN-2-YLAMINO)--BENZAMIDE	Cyclin-dependent kinase 2	IC 50 (nM)	64	7.5	30	Details
6-CYCLOHEXYLMETHYLOXY-2-(4'-HYDROXYANILINO)PURINE	Cyclin-dependent kinase 2	IC 50 (nM)	69	7.5	30	Details
6-O-Cyclohexylmethyl Guanine	Cyclin-dependent kinase 2	IC 50 (nM)	17000	7.5	30	Details
O6-CYCLOHEXYLMETHOXY-2-(4'-SULPHAMOYLANILINO) PURINE	Cyclin-dependent kinase 2	IC 50 (nM)	5.4	7.5	30	Details