“BRAF Inhibitors in Melanoma: Structural Insights, Therapeutic Resistance, and Biological Evaluation of Quinazoline Derivatives.”

Abstract

The Rapidly accelerated fibrosarcoma (RAF) kinase is important in the MAPK signalling pathway, maintaining various cellular functions, including cell division, metabolism, apoptosis, proliferation, etc. Due to the mutation of BRAF, one of the most prominent isoforms of RAF (a single point mutation), there is approximately a 70-90% chance of developing melanoma. Recent studies found that FDA-approved BRAF inhibitors such as Dabrafenib, Vemurafenib, and Encorafenib acquired resistance towards the therapy (It could be either intrinsic resistance or acquired resistance), furthermore, these candidates are involved in RAS-dependent paradoxical activation of the MAPK pathway. Therefore, the latest generation of chemotherapy drugs is increasingly aimed at targeting the allosteric pocket of BRAF to solve the following challenges. Over the past few years, various heterocyclic scaffolds have been designed to target and inhibit the mutant BRAFV600E regulations. So, in this review, we have analysed the BRAF structure, its activation process, downstream signalling pathway, mutation, the drugs capable of inhibiting the mutant BRAFV600E activity and the therapeutic adherence linked to the FDA-approved medications. We have particularly focused on the recent development of various quinazoline-based compounds with strong evidence covering structure-activity relationship, molecular docking and the key amino acid interactions that guide the researchers to design and synthesize novel Quinazoline analogues as potent BRAF inhibitors.