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Cyclins and cyclin-dependent kinases (Cdks) play important roles in regulation of the cell cycle. In particular, D-type cyclins, which are activated by rearrangement or amplification in several tumours, associate Cdk4/6. Cyclin D-Cdk4/6 complexes phosphorylate the retinoblastoma protein (pRB) and regulate the cell cycle during G 1 /S transition. Loss of function or deletion of p16 ink4a (endogenous Cdk4/6 specific inhibitor protein) frequently occurs in clinical cancer cells. As a next generation of Cdk inhibitors, selective inhibitors of only one target Cdk are expected to cause cell cycle arrest specifically. Suppression of tumour growth by G 1 arrest is thought to reduce the stress for normal cells more than in other phases, because normal cells are usually resting in the G 0 -G 1 phase. Thus, the design of Cdk4 selective inhibitors that cause cell cycle arrest in the G 1 phase has been attempted [2] (Structure-based generation of a new class of potent Cdk4 inhibitors: New de novo design strategy and library design, Honma, T. et. al., J. Med. Chem., 44, (2001), 4615-4627). To obtain highly selective and potent Cdk4 inhibitors a structure-based design was performed which consisted of lead generation of a new class of Cdk4 inhibitors based on a Cdk4 homology model, and enhancement of Cdk4 selectivity of lead compounds over Cdk1/2 and other kinases based on the binding modes and structural differences between Cdk4 and other kinases. This methodology was applied to search the Available Chemicals Directory and 382 commercial compounds were selected for screening in cyclin D-Cdk4 assays at concentrations up to 1mM. From this set, 18 compounds were found which possessed an IC 50 value of under 500 ยตM. From these hits, a class of diarylureas were identified with the potential for parallel synthesis follow up to validate the potential of the scaffold and to obtain preliminary SAR. 410 Urea compounds were then designed and synthesised as singles in solution, the design based on the diarylurea hits, and they were screened in a Cdk4 inhibition assay. One of the most potent compounds isolated was (i) which possessed an IC 50 value of 34 nM. This work has utilised a structure-based lead generation approach consisting of homology modelling of the target protein, construction of a library of compounds, followed by modification of hits obtained based on predicted binding mode. This strategy has provided potent compounds from a new class of diarylurea Cdk4 inhibitors and may lay the foundation for further work to improve potency in this series.
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