(thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids (TTP)

To study CK2 inhibitory activity of substituted (thieno[2,3-d] pyrimidin-4-ylthio)carboxylic acids, 28 compounds of this class were synthesized and tested in vitro. The most active compound obtained is TTP22 (3-{[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid) having IC₅₀ values of 0.1 µM. Kinetic studies of this compound showed that their activity towards human CK2 is a result of their competition with ATP molecule for the protein kinase binding site. Initial in vitro tests of discovered thienopyrimidine inhibitors TTP22 on four serine/threonine (ASK1, JNK3, AuroraAand Rock 1) and three tyrosine protein kinases (FGFR1, Met and Tie2) revealed remarkable specificity towards CK2. Structure-activity relationships of 28 tested thienopyrimidine derivatives have been studied and binding mode of this chemical class has been predicted.

Figure 1. The binding mode of TTP22 in the CK2 active site. Hydrogen bonds are shown by the dotted lines.

The importance of carboxyl group in the structure of CK2 inhibitors and role of sterical effects in their binding interactions has been shown providing the basis for further structural optimization of this chemical class.

• Synthesis and biological evaluation of substituted (thieno[2,3-d] pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2. Golub AG, Bdzhola VG, Briukhovetska NV, Balanda AO, Kukharenko OP, Kotey IM, Ostrynska OV, Yarmoluk SM. Eur. J. Med. Chem. 2011, 46 (3): 870-876.