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

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 10e potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.