The BRAFV600E mutation is one of the most clinically significant oncogenic drivers, appearing in cancers such as melanoma, thyroid cancer, and colorectal cancer. To address this, we designed a new series of pyrimidine–sulfonamide hybrid molecules, inspired by FDA-approved BRAF inhibitors (sorafenib, dabrafenib, and vemurafenib).

Using high-performance computing (HPC), we performed molecular docking and all-atom molecular dynamics simulations to evaluate how these compounds interact with the BRAFV600E protein in its αC-OUT/DFG-IN conformation. A total of 18 compounds (B1–B18) were synthesized and characterized.

We then assessed:

• BRAFV600E kinase inhibition

• Anticancer activity across HCT-116, A375, HT-29, and TPC-1 cell lines

Key findings:

• B14 showed strong cytotoxicity against HCT-116

• B8 was most effective against A375

• B18 showed potent inhibition in HT-29

• B3 demonstrated the strongest effect in TPC-1

• All four matched the performance of sorafenib

• B4 emerged as the most potent BRAFV600E kinase inhibitor

Why this matters:This work demonstrates how supercomputing accelerates rational drug design, helping identify promising therapeutic candidates more efficiently and at lower cost.

Read the paper:: https://doi.org/10.1007/s10822-025-00690-5

Title: Pyrimidin-4-bromobenzenesulfonamide/-4-nitrobenzenesulfonamide hybrids as potential BRAFV600E inhibitors: experimental, computational and biological evaluations

Research supported by the Croatian Science Foundation (IP-2022-4658) and powered by the Supek supercomputer at SRCE, University of Zagreb.