Biopolym. Cell. 2021; 37(1):62-72.
http://dx.doi.org/10.7124/bc.000A4C
Bioorganic Chemistry
Evaluation of in vitro activity and SAR study of the novel hetarylamino-3-aryl-1H-indazole derivatives as inhibitors of protein kinase CK2
1Protopopov M. V., 1Vdovin V. S., 1Lukashov S. S., 1Ostrynska O. V., 1, 2Borysenko I. P., 1Borovykov O. V., 1Starosyla S. A., 3Bilokin Y. V., 1Kukharenko O. P., 1Bdzhola V. G., 1Yarmoluk S. M.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. LLC “Scientific and service firm “Otava”
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  3. OTAVA Ltd
    400 Applewood Crescent, Unit 100, Vaughan, Ontario, L4K 0C3 Canada

Abstract

Aim. To identify novel protein kinase CK2 inhibitors among the 5-hetarylamino-1H-indazoles. Methods. Biochemical testing was carried out with the aid of γ-32P ATP in vitro kinase assay. Molecular docking via the Autodock 4.2.6 program package was executed, rescoring of docking results was performed using DrugScore scoring function. Results. Among the 17 studied 5-amino-3-arylindazole derivatives 11 inhibitors of protein kinase CK2 with IC50 in nanomolar range were identified. The most active compound has IC50 = 2 nM. SAR study and additional molecular modeling of these compounds allowed us to select prospective substituents for construction of novel compounds with improved activity and physicochemical properties. Conclusions. As a result of this work 11 nanomolar protein kinase CK2 inhibitors were developed and the binding modes of these compounds with the ATP-acceptor site were proposed using molecular docking methods. The physicochemical properties and SAR of substituents of studied compounds were analyzed and 6 novel compounds were designed for further development as protein kinase CK2 inhibitors. Summarizing, 5-heterylamino-1H-indazoles are a good basis for further CK2 inhibitors development.
Keywords: protein kinase CK2 inhibitor, in vitro kinase assay, molecular docking, indazole, pyrazolo[3,4-d]pyrimidine
Full text: (PDF, in English)

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