@article{Schonbrunn13, author={Ernst Schonbrunn and Stephane Betzi and Riazul Alam and Martin P. Martin and Andreas Becker and Huijong Han and Rawle Francis and Ramappa Chakrasali and Sudhakar R. Jakkaraj and Aslamuzzaman Kazi and Said M. Sebti and Christopher L. Cubitt and Anthony W. Gebhard and Lori Hazlehurst and Joseph Sherwin Tash and Gunda I. Georg}, title={Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases}, journal={J. Med. Chem.}, volume={56}, pages={3768--3782}, year={2013}, url={https://doi.org/10.1021/jm301234k}, doi={10.1021/jm301234k}, abstract={Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC$_{50}$ = 0.0009 – 0.0015 $\mu$M) from a single hit compound with weak inhibitory activity (IC$_{50}$ = 15 $\mu$M), discovered by high-throughput screening. Structure-based design was performed using 35 co-crystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4 and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC$_{50}$ values between 0.27 and 6.9 $\mu$M, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.}
}
![[abstract]](/huijong/biblio/img/abstract.gif)
[abstract]![[link]](/huijong/biblio/img/link.gif)
doi:10.1021/jm301234k