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Discovery of BRAF/HDAC Dual Inhibitors Suppressing Proliferation of Human Colorectal Cancer Cells
- Source :
- Frontiers in Chemistry, Vol 10 (2022)
- Publication Year :
- 2022
- Publisher :
- Frontiers Media S.A., 2022.
-
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.
- Subjects :
- BRAF
histone deacetylase
dual inhibitor
colorectal cancer
HDAC
Chemistry
QD1-999
Subjects
Details
- Language :
- English
- ISSN :
- 22962646
- Volume :
- 10
- Database :
- Directory of Open Access Journals
- Journal :
- Frontiers in Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.6a7b82a61177447a944213ed46765845
- Document Type :
- article
- Full Text :
- https://doi.org/10.3389/fchem.2022.910353