Theoretical and biological study of new potential BRAFV600E inhibitors

CAMPOS L; GARIBOTTO F; PEREZ C; FALCON C; ALVAREZ SE; ENRIZ RD

Congreso; SAIC 2018; 2018

Around 50% of melanoma patients express the mutated proteinkinase BRAFV600E which in turn induces cell survival and proliferationthrough ERK pathway activation. Lately, two small BRAFinhibitors (BRAFi) have been approved for the treatment of metastaticmelanoma: VemurafenibandDabrafenib. Consideringthattumorsbecomeresistantafterafewmonthsoftreatmentandinsomecasestumors are intrinsically resistant to BRAFi, new therapeuticoptions should be analyzed. Thus, by a combination of theoreticaland experimental studies our aim was to find new potential BRAFinhibitors. Based on virtual screening, docking and molecular dynamicsapproachesweselectedapanelof20differentcompounds.Totestits potential BRAFi activity, biological assays were conductedin melanoma cell line Lu1205 which express the mutant kinase BRAFV600E, and Vemurafenib was employed as positive control of all the experiments performed. In particular, ERK phosphorylation,an indirect measure of BRAFV600E activity, was determinedby western blot. In addition, MTT assay was conducted to studythe effect of the compounds on cell viability. Our results show that6-OH-2-carboxianilide derivatives 10C and 10F reduce significantlyERK phosphorylation at 1 μM (p