Design, Synthesis, and Bioactivity Assessment of Modified Vemurafenib Analog.

Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF mutation, for which vemurafenib, a selective BRAF inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. In this study, we designed, synthesized, and characterized five novel vemurafenib analogs-RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B-with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. All compounds induced apoptosis in BRAF-mutated A375 cells, with RF-86A displaying the lowest IC value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance.