Discovery of 2-Amino-7-sulfonyl-7 H -pyrrolo[2,3- d ]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation.

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-7 H -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 FGFR4 V550L and Ba/F3-TEL-FGFR4 V550L 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.