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Development of Highly Potent and Selective Diaminothiazole Inhibitors of Cyclin-Dependent Kinases

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Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, United States
Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
§ Translational Research Laboratory, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, United States
Molecular Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, United States
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, United States
*For E.S: phone, +813-745-4503; e-mail, [email protected]. For G.I.G.: phone, +612-626-6320; e-mail, [email protected]
Cite this: J. Med. Chem. 2013, 56, 10, 3768–3782
Publication Date (Web):April 19, 2013
Copyright © 2013 American Chemical Society

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    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.

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    X-ray crystallography data and refinement statistics, FoFc electron density omit maps, additional SAR data along with dose–response graphs, kinase profiling results, and NMR spectra. This material is available free of charge via the Internet at

    Accession Codes

    The atomic coordinates and structure factors for the crystal structures determined as part of this work have been deposited in the Protein Data Bank (entries 3QQK, 3R8V, 3QTQ, 3R8U, 3S00, 3S0O, 3R8Z, 3QTR, 3RJC, 3R9N, 3RAH, 3QTW, 3QTS, 3RPR, 3RZB, 3QU0, 3RK7, 3RK9, 3RKB, 3RK5, 3QXP, 3QTZ, 3QTU, 3QTX, 3RPV, 3RAL, 3RAK, 3RPY, 3SQQ, 3S1H, 3RMF, 3RNI, 3R9D, 3R9O, 3R9H, and 4GCJ).

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