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.
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