PDBsum entry 1oiu

Kinase

PDB id: 1oiu

Contents

Protein chains

297 a.a. *

256 a.a. *

266 a.a. *

Ligands

N76 ×2

SGM ×2

Metals

_MG

Waters ×646

* Residue conservation analysis

References listed in PDB file

Key reference

• Title: N2-Substituted o6-Cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-Dependent kinases 1 and 2.
• Authors: I.R.Hardcastle, C.E.Arris, J.Bentley, F.T.Boyle, Y.Chen, N.J.Curtin, J.A.Endicott, A.E.Gibson, B.T.Golding, R.J.Griffin, P.Jewsbury, J.Menyerol, V.Mesguiche, D.R.Newell, M.E.Noble, D.J.Pratt, L.Z.Wang, H.J.Whitfield.
• Ref.: J Med Chem, 2004, 47, 3710-3722. [DOI no: 10.1021/jm0311442]
• PubMed id: 15239650

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.