Phenotypic hit becomes first RPB12-targeting thiazolidinone for colorectal cancer
- A thiazolidinone hit from a phenotypic screen was optimized with metabolism-guided modifications, yielding compound B9.
- B9 preferentially suppressed colorectal cancer cells over normal colonic epithelial cells and curbed colony formation, spheroid growth and migration/invasion phenotypes.
- Activity-based protein profiling nominated RPB12 as the target, supported by knockdown, CETSA, DARTS, SPR and docking.
- B9 reduced tumor growth in vivo without evident toxicity, positioning RPB12 as a new CRC target.
💡 Points Based on the abstract
A thiazolidinone hit makes me check for promiscuity first: this class is notorious for reactive or assay-interfering behavior, so ABPP-nominated targets need a close inactive analog and a binding-site mutant to prove RPB12 engagement. Also, RPB12 is a small subunit shared by RNA polymerases, so how a cancer-selective window arises is the question I'd want answered.
Thiazolidinones as Potential Inhibitors to Target RPB12 for Treatment of Colorectal Cancer Growth ↗