LAUSR

Fibroblast growth factor receptors (FGFRs) play key roles in promoting cancer cell proliferation, differentiation, and migration. However, acquired resistance to FGFR inhibitors has become an emerging challenge in long-term cancer therapies, especially for hepatocellular carcinoma (HCC). Gatekeeper (GK) mutations are the main mechanism of resistance. Herein, we describe the discovery of a series of reversible FGFR inhibitors, particularly for GK mutations with the 2-amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine scaffold. Rational design, optimization, and pharmacokinetic screening provided representative compound 19 with potent FGFR inhibition in vitro, high bioavailability, and an acceptable half-life. GK mutation tolerance was supported by assays against FGFR4V550L and Ba/F3-TEL-FGFR4V550L cells. Moreover, compound 19 exhibited potent antitumor potency in HUH7 xenograft mouse models with no obvious toxicity observed. Compound 19 was identified as a potential candidate for overcoming GK mutations for HCC treatment.