Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer

Journal of Medicinal Chemistry
2022.0

Abstract

The activation of the STAT signal after incubation with the HDAC inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound <b>10e</b> potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that <b>10e</b> also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, <b>10e</b> significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that <b>10e</b> could be a new drug candidate for malignant tumors.

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