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

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
J Med Chem 56 3768-82 (2013)

Cited: 30 times
EuropePMC logo PMID: 23600925

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 IC50 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.

Articles - 3rjc mentioned but not cited (1)

  1. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. 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. J Med Chem 56 3768-3782 (2013)


Reviews citing this publication (5)

  1. Mitigating risk in academic preclinical drug discovery. Dahlin JL, Inglese J, Walters MA. Nat Rev Drug Discov 14 279-294 (2015)
  2. The essential roles of chemistry in high-throughput screening triage. Dahlin JL, Walters MA. Future Med Chem 6 1265-1290 (2014)
  3. Development and therapeutic potential of 2-aminothiazole derivatives in anticancer drug discovery. Alizadeh SR, Hashemi SM. Med Chem Res 30 771-806 (2021)
  4. Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†. Faber EB, Wang N, Georg GI. Biol Reprod 103 357-367 (2020)
  5. Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer's Disease: Can It Work from a Molecular Point of View? Czarnota-Łydka K, Kucwaj-Brysz K, Pyka P, Haberek W, Podlewska S, Handzlik J. Int J Mol Sci 23 8768 (2022)

Articles citing this publication (24)



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