Rigidified pyrazine-oxadiazole scaffold yields FGFR2 inhibitors that spare FGFR1 and FGFR4
- Starting from a known FGFR inhibitor scaffold, the team combined bioisosteric swaps with co-crystal structures to arrive at a pyrazine-oxadiazole core aimed at FGFR2 selectivity.
- The lead, 10c, showed moderate preference over FGFR1 and a much larger margin over FGFR4, targeting the hyperphosphatemia and diarrhea liabilities of pan-FGFR drugs.
- In cells it curbed proliferation and blocked FGFR2 downstream signaling; in a SNU-16 gastric cancer xenograft it was efficacious without notable weight loss.
💡 Points Based on the abstract
FGFR1 and FGFR2 share nearly identical ATP pockets, so a modest FGFR1 margin is the number I'd scrutinize; without a kinome panel and cellular selectivity (e.g. FGFR1-driven lines), I wouldn't call it isoform-selective. Rigidification is a sensible way to buy selectivity, but I'd want gatekeeper-mutant (V565) activity and a head-to-head against pemigatinib or futibatinib before getting excited.