Scaffold-hopping screen yields a 2-OG-noncompetitive KDM6B inhibitor active in cervical cancer xenografts
- Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
- The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
- Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.
💡 Points
Most JmjC inhibitors live or die on 2-OG-site chemistry and its polarity baggage, so a non-competitive series is a genuinely different starting point. I'd want to know why enzyme-level pan-KDM activity collapses to H3K27me3 selectivity in cells, and what the guanidine does to permeability.