4CFN

Structure-based design of C8-substituted O6-cyclohexylmethoxyguanine CDK1 and 2 inhibitors.

Summary for 4CFN

• Entry DOI: 10.2210/pdb4cfn/pdb
• Related: 1W8C 4CFM 4CFU 4CFV 4CFW 4CFX
• Descriptor: CYCLIN-DEPENDENT KINASE 2, CYCLIN-A2, 6-(cyclohexylmethoxy)-8-(trifluoromethyl)-9H-purin-2-amine, ... (5 entities in total)
• Functional Keywords: cell cycle, cyclin dependent kinases, structure-based drug design, conformational restraint, reversed binding mode
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus: P20248
• Total number of polymer chains: 4
• Total formula weight: 128897.22

Authors

Carbain, B.,Paterson, D.J.,Anscombe, E.,Campbell, A.,Cano, C.,Echalier, A.,Endicott, J.,Golding, B.T.,Haggerty, K.,Hardcastle, I.R.,Jewsbury, P.,Newell, D.R.,Noble, M.E.M.,Roche, C.,Wang, L.Z.,Griffin, R. (deposition date: 2013-11-19, release date: 2013-12-18, Last modification date: 2023-12-20)

Primary citation

Carbain, B.,Paterson, D.J.,Anscombe, E.,Campbell-Dexter, A.,Cano, C.,Echalier, A.,Endicott, J.,Golding, B.T.,Haggerty, K.,Hardcastle, I.R.,Jewsbury, P.J.,Newell, D.R.,Noble, M.,Roche, C.,Wang, L.,Griffin, R.J.
8-Substituted O6-Cyclohexylmethylguanine Cdk2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.
J.Med.Chem., 57:56-, 2014

PubMed 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.

PubMed: 24304238
DOI: 10.1021/JM401555V

Experimental method

X-RAY DIFFRACTION (2.2 Å)