In:
ChemMedChem, Wiley, Vol. 12, No. 22 ( 2017-11-22), p. 1857-1865
Abstract:
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 50 22 n m ; GSK2163632A) and the pyrimidine 17 (IC 50 31 n m ; 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 50 66 n m ; 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201700503
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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