Pyranopyrazole scaffold gives selective carbonic anhydrase IX inhibitors with combination potential
- Pyrano[2,3-c]pyrazole derivatives were designed and synthesized to overcome the difficulty of achieving isoform selectivity among closely related carbonic anhydrases.
- Several analogues showed strong, selective activity against the tumor-associated hCA IX; compound 12 stood out, and computational modeling helped explain its binding mode.
- Compound 12 acted synergistically with the GPX4 inhibitor RSL3 in pancreatic cancer cells, and affected migration and markers tied to autophagy, metabolism and EMT.
💡 Points
Pyranopyrazole is a fresh, easily decorated chemotype, so it dodges the sulfonamide zinc-binder crowd, and that's worth a look since SLC-0111-type ureido-sulfonamides keep struggling with CA I/II off-target hits. What I'd want next: selectivity numbers against CA XII and in hypoxic cells, because the RSL3 synergy is only phenotypic until on-target CA IX engagement is shown in cells.