Kotey I. New inhibitors of protein kinases FGFR1 and CK2 based on the derivatives of thieno[2,3-d]pyrimidine

New inhibitors of protein kinases FGFR1 and CK2 based on the derivatives of thieno[2,3-d]pyrimidine. The search of new inhibitors of FGFR1 and CK2 using methods of molecular modeling, chemical synthesis and biochemical testing. The molecular docking, biochemical testing, chemical synthesis, TLC, LC MS, NMR spectrometry. In order to discover novel FGFR1 inhibitors we have performed molecular docking of chemical library containing about 2000 ligands and selected 35 compounds for in vitro testing. We have synthesized 33 derivatives of N-phenylthieno[2,3-d]pyrimidin-4-amine and tested for inhibitory activity toward FGFR1. Among these compounds we have identified 23 inhibitors of FGFR1 with IC50 values in the range from 0,16 µM to 18,2 µM. Since a number of efficient CK2 inhibitors contain carboxyl group, we have synthesized 28 derivatives of (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acid and tested for inhibitory activity toward CK2. Among these compounds we have identified 21 inhibitors of protein kinase CK2 with IC50 values in the range from 0,1 µM to 30 µM. Structure-activity relationships (SAR) of the synthesized compounds were studied. The established binding models were used for prediction of the ways for further chemical optimization with the aim to obtain more active inhibitors. As a result of this optimization 7 highly effective nanomolar CK2 inhibitors have been developed, among them three compounds demonstrated high selectivity toward CK2 and can be used in further research to study structure and cellular functions of this protein kinase. The binding models of inhibitors with protein kinases and SAR can be used for the development of novel highly potent protein kinase inhibitors. Scope – bioorganic chemistry.