Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2)

5 years ago

Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis-Specific Serine/Threonine Kinase 2 (TSSK2)

Gunda Georg, John Herr, Jagathpala Shetty, Rondedrick Sinville, Jon Hawkinson, Timothy Ward, Deepti Mudaliar

Testis-specific serine/threonine kinase 2 (TSSK2) is an important target for reversible male contraception. A high-throughput screen of ~17,000 compounds using a mobility shift assay identified two potent series of inhibitors having a pyrrolopyrimidine or pyrimidine core. The pyrrolopyrimidine 10 (IC50 22 nM) and the pyrimidine 17 (IC50 31 nM) are the most potent TSSK2 inhibitors in these series. Except for the broad kinase inhibitor staurosporine, these series contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported. Compounds in these pyrrolopyrimidine and pyrimidine series are reported to have higher inhibitory potencies against kinases other than TSSK2. The novel, potent TSSK2 inhibitor compound 19 lacking the potential for metabolic activation was found to be a more potent inhibitor of ALK, FAK, IRR and FAK. Despite the sequence homology of TSSK family members, a wide range of inhibitory potencies was found for compound 19 with the rank order potency TSSK1 > TSSK2 > TSSK3 > TSSK6. These results indicate the possibility of identifying potent dual inhibitors of TSSK1 and TSSK2, which may be required for a complete contraceptive effect. The future availability of a TSSK2 crystal structure will facilitate structure-based discovery of selective TSSK inhibitors from these pyrrolopyrimidine and pyrimidine scaffolds.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700503