4.7 Article

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

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume -, Issue -, Pages -

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01420

Keywords

-

Funding

  1. China Pharmaceutical University [CPU2018GF02]

Ask authors/readers for more resources

The study describes the discovery of a series of reversible FGFR inhibitors, particularly targeting the acquired resistance caused by GK mutations. Compound 19 exhibits potent in vitro FGFR inhibition, high bioavailability, and an acceptable half-life, making it a potential candidate for overcoming GK mutations in hepatocellular carcinoma treatment.
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 pharmacoki-netic 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available