Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells

Li，Yingjun1; Huang，Yongjun2; Cheng，Huimin3; Xu，Fang2; Qi，Ruxi4; Dai，Botao1; Yang，Yujian1; Tu，Zhengchao5; Peng，Lijie2; Zhang，Zhang2

2022-07-22

10.3389/fchem.2022.910353

Frontiers in Chemistry   Impact Factor & Quartile

2296-2646

2296-2646

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 BRAF 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.

BRAF colorectal cancer dual inhibitor HDAC histone deacetylase

SCI

English

First ; Corresponding

Guangdong Basic and Applied Basic Research Foundation[2020A1515110361] ; National Natural Science Foundation of China["82150206","81973158"] ; Ministry of Science and Technology of the People's Republic of China[SQ2019YFE010401] ; Natural Science Foundation of Guangdong Province[2019A1515011235] ; Guangzhou Municipal Science and Technology Bureau[202002030414]

Chemistry

Chemistry, Multidisciplinary

WOS:000837069400001

FRONTIERS MEDIA SA

2-s2.0-85135491472

Scopus

1.Academy for Advanced Interdisciplinary Studies and Department of Chemistry,Southern University of Science and Technology,Shenzhen,China
2.International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education,Guangzhou City Key Laboratory of Precision Chemical Drug Development,School of Pharmacy,Jinan University,Guangzhou,China
3.Shenzhen Jingtai Technology Co.,Ltd,Shenzhen,China
4.Cryo-EM Center,Southern University of Science and Technology,Shenzhen,China
5.Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou,China

Li，Yingjun,Huang，Yongjun,Cheng，Huimin,et al. Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells[J]. Frontiers in Chemistry,2022,10.

Li，Yingjun.,Huang，Yongjun.,Cheng，Huimin.,Xu，Fang.,Qi，Ruxi.,...&Zhang，Zhang.(2022).Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells.Frontiers in Chemistry,10.

Li，Yingjun,et al."Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells".Frontiers in Chemistry 10(2022).