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

Yingjun Li; Yongjun Huang; Huimin Cheng; Fang Xu; Ruxi Qi; Botao Dai; Yujian Yang; Zhengchao Tu; Lijie Peng; Zhang Zhang

doi:10.3389/fchem.2022.910353

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

Front Chem. 2022 Jul 22:10:910353. doi: 10.3389/fchem.2022.910353. eCollection 2022.

Authors

Yingjun Li¹, Yongjun Huang², Huimin Cheng³, Fang Xu², Ruxi Qi⁴, Botao Dai¹, Yujian Yang¹, Zhengchao Tu⁵, Lijie Peng², Zhang Zhang²

Affiliations

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 (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China.
³ XtalPi Inc., (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.

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 BRAF^V600E 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.

Keywords: BRAF; HDAC; colorectal cancer; dual inhibitor; histone deacetylase.