Pyrimidin-4-bromobenzenesulfonamide/-4-nitrobenzenesulfonamide hybrids as potential BRAF^V600E inhibitors:...

BRAF mutations were first discovered by Davies et al. in 2002. BRAF^V600E mutation is the most prevalent, accounting for approximately 90% of all BRAF mutations. BRAF^V600E mutations have been identified at varying frequencies across multiple human cancers, including malignant melanoma (70-90%), thyroid cancer (45-50%), colorectal cancer (5-20%), and others. In this study, we designed a series of pyrimidine-sulfonamide hybrids, inspired by first- and second-generation FDA-approved BRAF inhibitors such as sorafenib, dabrafenib, and vemurafenib. The designed compounds were intended to target the αC-OUT/DFG-IN conformation of the BRAF^V600E mutant protein. Eighteen compounds (B1-B18) were synthesized and characterized using spectral techniques. Molecular docking and MD simulations were carried out to assess their binding affinity and stability with the BRAF^V600E protein. Kinase inhibition was assessed using a BRAF^V600E specific assay, and anticancer activity was tested against HCT-116, A375, HT-29, and TPC-1 cell lines. Among the tested derivatives, B14 exhibited the highest cytotoxicity against HCT-116, B8 was most effective against A375, B18 showed potent inhibition in HT-29, and B3 demonstrated the strongest activity in TPC-1 cells. All four compounds exhibited activity comparable to sorafenib. Notably, B4 emerged as the most potent BRAF^V600E kinase inhibitor in assays.