4CFX

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

4CFX の概要

• エントリーDOI: 10.2210/pdb4cfx/pdb
• 関連するPDBエントリー: 4CFM 4CFN 4CFU 4CFV 4CFW
• 分子名称: CYCLIN-DEPENDENT KINASE 2, CYCLIN-A2, 3-[2-amino-6-(cyclohexylmethoxy)-7H-purin-8-yl]benzenesulfonamide, ... (4 entities in total)
• 機能のキーワード: cell cycle, structure-based drug design, conformational restraint, reversed binding mode
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus : P20248
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129475.82

構造登録者

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. (登録日: 2013-11-19, 公開日: 2014-12-10, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.5 Å)