Hawkinson Jon E, Sinville Rondedrick, Mudaliar Deepti, Shetty Jagathpala, Ward Timothy, Herr John C, Georg Gunda I
Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55414, USA.
Department of Cell Biology, Center for Research in Contraceptive and Reproductive Health, University of Virginia, Charlottesville, VA, 22908, USA.
ChemMedChem. 2017 Nov 22;12(22):1857-1865. doi: 10.1002/cmdc.201700503. Epub 2017 Oct 20.
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 (IC 22 nm; GSK2163632A) and the pyrimidine 17 (IC 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 (IC 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.
睾丸特异性丝氨酸/苏氨酸激酶2（TSSK2）是可逆性男性避孕的重要靶点。使用迁移率变动分析对约17000种化合物进行的高通量筛选鉴定出了两个具有吡咯并嘧啶或嘧啶核心的强效抑制剂系列。吡咯并嘧啶10（IC50为22 nm；GSK2163632A）和嘧啶17（IC50为31 nm；ALK抑制剂1）是这些系列中最有效的TSSK2抑制剂，除了广泛的激酶抑制剂星形孢菌素外，它们是报道的任何TSSK亚型的首个亚100纳摩尔抑制剂。新型强效嘧啶TSSK2抑制剂化合物19（IC50为66 nm；2-[[5-氯-2-[2-甲氧基-4-(1-甲基哌啶-4-基)苯胺基]嘧啶-4-基]氨基]-N-甲基苯磺酰胺）没有代谢活化的可能性。化合物19对TSSK1、TSSK2、TSSK3、TSSK6的抑制效力排序为TSSK1>TSSK2>TSSK3>TSSK6，这表明可以鉴定出强效的TSSK1/2双重抑制剂，这可能是实现完全避孕效果所必需的。未来TSSK2晶体结构的可得性将有助于从这些吡咯并嘧啶和嘧啶支架中基于结构发现选择性TSSK抑制剂。
