Li Yingjun, Huang Yongjun, Cheng Huimin, Xu Fang, Qi Ruxi, Dai Botao, Yang Yujian, Tu Zhengchao, Peng Lijie, Zhang Zhang
Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen, China.
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.
Front Chem. 2022 Jul 22;10:910353. doi: 10.3389/fchem.2022.910353. eCollection 2022.
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)--hydroxyalkanamide derivatives were designed and synthesized as novel dual inhibitors of BRAF and HDACs using a pharmacophore hybrid strategy. In particular, compound 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 as a promising lead molecule for further development and a useful tool for studying the effects of BRAF/HDAC dual inhibitors.
组蛋白去乙酰化酶抑制剂与BRAF抑制剂（BRAFi）联合使用已显示出可增强抗肿瘤作用并减缓BRAFi耐药性的进展。在本研究中，采用药效团杂合策略设计并合成了一系列（噻唑-5-基）嘧啶-2-基）氨基）-羟基链烷酰胺衍生物，作为BRAF和组蛋白去乙酰化酶（HDAC）的新型双重抑制剂。特别是，化合物对BRAF、HDAC1和HDAC6酶具有强效活性。它能有效抑制携带BRAF突变的HT-29细胞以及具有野生型BRAF的HCT116细胞的增殖。在这两种细胞中均验证了对BRAF和HDAC下游蛋白的双重抑制作用。总体而言，这些结果支持该化合物作为一个有前景的先导分子用于进一步开发，以及作为研究BRAF/HDAC双重抑制剂作用的有用工具。
