Discovery and development of quinazoline compounds as irreversible pan-fibroblast growth factor receptor inhibitors with potent antitumor activities

Abstract

Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of multiple cancer types. Therefore, it is an attractive target for tumor therapy, and many efforts have been directed to the discovery of irreversible FGFR inhibitors over the last decade. Using a quinazoline scaffold, we used structure-based drug design to obtain a series of novel covalent pan-FGFR inhibitors. One of the representative compounds, I-11, showed remarkable enzymatic activity toward FGFR1–4 (FGFR1/2/3/4, IC50 = 5.6/2.2/8.5/4.6 nM) and strongly suppressed the proliferation of Huh7 HCC cells (IC50 = 6.35 nM). Further, I-11 exhibited reasonable PK profiles (F = 57.5 %) and showed significant antitumor effects in the Huh-7 xenograft model without obvious changes in body weight. Overall, I-11 was identified as a potential pan-FGFR inhibitor for cancer therapy and deserved further research.