Discovery of Biaryl amide-containing transmembrane serine protease 2 (TMPRSS2) inhibitors for the treatment of prostate Cancer.

Transmembrane serine protease 2 (TMPRSS2) is an important driver of prostate tumor progression and represents a promising therapeutic target for prostate cancer treatment. Guided by the lead scaffold avoralstat, we designed and synthesized a series of novel compounds to systematically explore their structure-activity relationships (SARs) against TMPRSS2. Among them, compound XDTM13 (IC50 = 3.60 nM) and XDTM14 (IC50 = 34.6 nM) exhibited potent TMPRSS2 inhibitory activity, with XDTM13 demonstrating markedly superior potency compared to avoralstat (IC50 = 18.2 nM). Western blot analysis confirmed that XDTM13 and XDTM14 effectively suppressed TMPRSS2 autoproteolysis, while transwell assays further demonstrated their inhibition of LNCaP cell migration and invasion. Furthermore, XDTM13 and XDTM14 showed improved metabolic stability in human liver microsomes relative to avoralstat. Collectively, these results indicate that XDTM13 and XDTM14 are promising lead compounds for TMPRSS2 inhibition, with XDTM13 emerging as a particularly potent candidate for further development.