1W8C
CO-CRYSTAL STRUCTURE OF 6-CYCLOHEXYLMETHOXY-8-ISOPROPYL-9H-PURIN-2- YLAMINE AND MONOMERIC CDK2
Summary for 1W8C
| Entry DOI | 10.2210/pdb1w8c/pdb |
| Related | 4CFM 4CFN 4CFU 4CFV 4CFW 4CFX |
| Descriptor | CELL DIVISION PROTEIN KINASE 2, 6-(CYCLOHEXYLMETHOXY)-8-ISOPROPYL-9H-PURIN-2-AMINE (3 entities in total) |
| Functional Keywords | transferase, cell cycle, phosphorylation, mitosis, inhibition, cell division |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 34323.90 |
| Authors | Pratt, D.J.,Endicott, J.A.,Noble, M.E.M. (deposition date: 2004-09-20, release date: 2006-08-30, Last modification date: 2024-10-16) |
| 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 Cited by 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: 24304238DOI: 10.1021/JM401555V PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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