Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.

Article Details

Citation

Copy to clipboard

McInnes C, Wang S, Anderson S, O'Boyle J, Jackson W, Kontopidis G, Meades C, Mezna M, Thomas M, Wood G, Lane DP, Fischer PM

Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors.

Chem Biol. 2004 Apr;11(4):525-34.

PubMed ID

15123247 [ View in PubMed

]

Abstract

A number of selective inhibitors of the CDK4/cyclin D1 complex have been reported recently. Due to the absence of an experimental CDK4 structure, the ligand and protein determinants contributing to CDK4 selectivity are poorly understood at present. Here, we report the use of computational methods to elucidate the characteristics of selectivity and to derive the structural basis for specific, high-affinity binding of inhibitors to the CDK4 active site. From these data, the hypothesis emerged that appropriate incorporation of an ionizable function into a CDK2 inhibitor results in more favorable binding to CDK4. This knowledge was applied to the design of compounds in the otherwise CDK2-selective 2-anilino-4-(thiazol-5-yl)pyrimidine pharmacophore that are potent and highly selective ATP antagonists of CDK4/cyclin D1. The findings of this study also have significant implications in the design of CDK4 mimic structures based on CDK2.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N'-(Pyrrolidino[2,1-B]Isoindolin-4-On-8-Yl)-N-(Pyridin-2-Yl)Urea	Cyclin-dependent kinase 2	IC 50 (nM)	96	N/A	N/A	Details