AUTHOR=Li Yingjun , Huang Yongjun , Cheng Huimin , Xu Fang , Qi Ruxi , Dai Botao , Yang Yujian , Tu Zhengchao , Peng Lijie , Zhang Zhang TITLE=Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells JOURNAL=Frontiers in Chemistry VOLUME=10 YEAR=2022 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.910353 DOI=10.3389/fchem.2022.910353 ISSN=2296-2646 ABSTRACT=

The combination of histone deacetylase inhibitor and BRAF inhibitor (BRAFi) has been shown to enhance the antineoplastic effect and reduce the progress of BRAFi resistance. In this study, a series of (thiazol-5-yl)pyrimidin-2-yl)amino)-N-hydroxyalkanamide derivatives were designed and synthesized as novel dual inhibitors of BRAF and HDACs using a pharmacophore hybrid strategy. In particular, compound 14b possessed potent activities against BRAF, HDAC1, and HDAC6 enzymes. It potently suppressed the proliferation of HT-29 cells harboring BRAFV600E mutation as well as HCT116 cells with wild-type BRAF. The dual inhibition against BRAF and HDAC downstream proteins was validated in both cells. Collectively, the results support 14b as a promising lead molecule for further development and a useful tool for studying the effects of BRAF/HDAC dual inhibitors.