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

Jon E. Hawkinson, Rondedrick Sinville, Deepti Mudaliar, Jagathpala Shetty, Timothy Ward, John C. Herr, Gunda I. Georg

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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; GSK2163632A) and the pyrimidine 17 (IC50 31 nm; ALK inhibitor 1) are the most potent TSSK2 inhibitors in these series, which contain the first sub-100 nanomolar inhibitors of any TSSK isoform reported, except for the broad kinase inhibitor staurosporine. The novel, potent pyrimidine TSSK2 inhibitor compound 19 (IC50 66 nm; 2-[[5-chloro-2-[2-methoxy-4-(1-methylpiperidin-4-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) lacks the potential for metabolic activation. Compound 19 had a potency rank order of TSSK1>TSSK2>TSSK3>TSSK6, indicating that potent dual inhibitors of TSSK1/2 can be identified, 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.

Original languageEnglish (US)
Pages (from-to)1857-1865
Number of pages9
Issue number22
StatePublished - Nov 22 2017

Bibliographical note

Funding Information:
The authors dedicate this study to Prof. John C. Herr, a devoted scientist, friend, mentor, and colleague, who passed away during the conduct of this study. The PKIS was supplied by GlaxoSmith-Kline LLC and the Structural Genomics Consortium under an open access Material Transfer and Trust Agreement: http:// www.sgc-unc.org. These studies were supported by the US National Institutes of Health (NIH 1U01HD060491, 1U01HD076542, and HHSN275201300017C) from the Contraception Research Branch of NICHD and by Schering AG, Berlin.

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Copyright 2017 Elsevier B.V., All rights reserved.


  • high-throughput screening
  • kinase inhibitors
  • male contraception
  • structure–activity relationships
  • testis-specific serine/threonine kinase


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