Thiazolidinones as Potential Inhibitors to Target RPB12 for Treatment of Colorectal Cancer Growth
Yikai Xu, Jiangnan Ye, Donghui Sun, Xianghao Zhang, Weixiong Chen, Xinxin Liu, Jinhua Liu, Mingyao Liu, Meng Li, Zhengfang Yi, Shunying LiuAbstract
Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, and selective molecular targets and corresponding inhibitors remain insufficiently developed. Starting from a phenotypic screening hit, we performed systematic structural optimization guided by metabolism-guided modification, leading to the discovery of B9. B9 selectively inhibited HCT116 CRC cells and showed much weaker inhibition of normal colonic epithelial NCM460 cells (IC50 = 0.052 vs 1.114 μM). B9 also suppressed CRC clonogenic growth, 3D spheroid formation, and migration- and invasion-associated phenotypes in vitro. B9 achieved significant tumor growth inhibition (TGI = 80.1%) in vivo without obvious toxicity. RPB12 was identified as a candidate cellular target of B9 by activity-based protein profiling (ABPP) and validated by shRNA knockdown, CETSA, DARTS, SPR, and molecular docking. These findings support RPB12 as a novel promising target for the treatment of CRC and B9 as the first RPB12-targeting inhibitor for further development in CRC therapy.