Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases

Ernst Schonbrunn; Stephane Betzi; Riazul Alam; Mathew P. Martin; Andreas Becker; Huijong Han; Rawle Francis; Ramappa Chakrasali; Sudhakar Jakkaraj; Aslamuzzaman Kazi; Said M. Sebti; Christopher L. Cubitt; Anthony W. Gebhard; Lori A. Hazlehurst; Joseph S. Tash; Gunda I. Georg

doi:10.1021/jm301234k

Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases

Ernst Schonbrunn, Stephane Betzi, Riazul Alam, Mathew P. Martin, Andreas Becker, Huijong Han, Rawle Francis, Ramappa Chakrasali, Sudhakar Jakkaraj, Aslamuzzaman Kazi, Said M. Sebti, Christopher L. Cubitt, Anthony W. Gebhard, Lori A. Hazlehurst, Joseph S. Tash, Gunda I. Georg

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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 (IC₅₀ = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC₅₀ = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal 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 μM, 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.

Original language	English (US)
Pages (from-to)	3768-3782
Number of pages	15
Journal	Journal of medicinal chemistry
Volume	56
Issue number	10
DOIs	https://doi.org/10.1021/jm301234k
State	Published - May 23 2013

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Schonbrunn, E., Betzi, S., Alam, R., Martin, M. P., Becker, A., Han, H., Francis, R., Chakrasali, R., Jakkaraj, S., Kazi, A., Sebti, S. M., Cubitt, C. L., Gebhard, A. W., Hazlehurst, L. A., Tash, J. S., & Georg, G. I. (2013). Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. Journal of medicinal chemistry, 56(10), 3768-3782. https://doi.org/10.1021/jm301234k

Schonbrunn, E, Betzi, S, Alam, R, Martin, MP, Becker, A, Han, H, Francis, R, Chakrasali, R, Jakkaraj, S, Kazi, A, Sebti, SM, Cubitt, CL, Gebhard, AW, Hazlehurst, LA, Tash, JS & Georg, GI 2013, 'Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases', Journal of medicinal chemistry, vol. 56, no. 10, pp. 3768-3782. https://doi.org/10.1021/jm301234k

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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 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal 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 μM, 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.",

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AU - Han, Huijong

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AU - Chakrasali, Ramappa

AU - Jakkaraj, Sudhakar

AU - Kazi, Aslamuzzaman

AU - Sebti, Said M.

AU - Cubitt, Christopher L.

AU - Gebhard, Anthony W.

AU - Hazlehurst, Lori A.

AU - Tash, Joseph S.

AU - Georg, Gunda I.

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Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases

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