PDBsum entry 4cfm

Cell cycle

PDB id: 4cfm

Contents

Protein chains

297 a.a.

258 a.a.

267 a.a.

Ligands

4QE ×2

Waters ×10

References listed in PDB file

Key reference

• Title: 8-Substituted o(6)-Cyclohexylmethylguanine cdk2 inhibitors: using structure-Based inhibitor design to optimize an alternative binding mode.
• Authors: B.Carbain, D.J.Paterson, E.Anscombe, A.J.Campbell, C.Cano, A.Echalier, J.A.Endicott, B.T.Golding, K.Haggerty, I.R.Hardcastle, P.J.Jewsbury, D.R.Newell, M.E.Noble, C.Roche, L.Z.Wang, R.J.Griffin.
• Ref.: J Med Chem, 2014, 57, 56-70. [DOI no: 10.1021/jm401555v]
• PubMed id: 24304238

Abstract

Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.