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.
Zi-Jie Jin, Hao Yao, Jiang-Hui Ye et al.· Bioorganic chemistry (Print)· 0 citations
Plant nitrogen uptake and utilization are governed by a complex network involving nitrate transporters and signal-responsive genes. Here, we show that the high mobility group box 1 protein OsHMGB1 directly binds to the OsNRT2.2 promoter and functions as a transcriptional repressor, negatively regulating its expression. Knockout of OsHMGB1 upregulates OsNRT2.2 expression, leading to increased nitrate accumulation and enhanced tolerance to low-nitrogen (LN) conditions in rice seedlings. Furthermore, OsHMGB1 expression is significantly reduced in OsCBL1-knockdown (OsCBL1-KD) plants, suggesting its dependence on OsCBL1-mediated signaling. OsHMGB1 acts additively with OsCCA1, a known repressor that binds the OsNRT2.2 promoter, to negatively regulate OsNRT2.2 expression. Notably, sequence variation in the OsHMGB1 promoter between indica and japonica rice varieties correlates with lower expression levels in indica varieties, which are associated with higher nitrogen use efficiency (NUE)-related agronomic traits, specifically, greater grain yield and increased number of effective panicles, in indica varieties compared with japonica. Together, these findings identify OsHMGB1 as a key repressor of OsNRT2.2, associated with OsCBL1-dependent nitrate signaling and act additively with OsCCA1 to enhance LN tolerance, suggesting that OsHMGB1 expression levels correlate with NUE-related traits under LN conditions. This work elucidates a link between calcium signaling and nitrate response in rice.
Jiawei Niu, Yutan Guo, Jia-Qi Cheng et al.· International Journal of Bio...· 0 citations
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