THEORETICAL AND BIOLOGICAL STUDY OF NEW POTENTIAL BRAFV600E INHIBITORS

CAMPOS, LUDMILA E.; FRANCISCO GARIBOTTO; CELIA PEREZ; CRISTINA D CRUZ; ALVAREZ, SERGIO; ENRIZ, RICARDO DANIEL

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica ?SAIC. LXVI Reunión Anual de la Sociedad Argentina de Inmunología ?SAI. Reunión Anual de la Sociedad Argentina de Fisiología ?SAFIS?con la participación de Sociedad Argentina de Virolog; 2018

Sociedad Argentina de Fisiología y Sociedad Argentina de Virologia

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: Vemurafenib and Dabrafenib. Considering that tumorsbecome resistant after a few months of treatment and in somecases tumors 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 dynamicsapproaches we selected a panel of 20 different compounds.To test its potential BRAFi activity, biological assays were conductedin melanoma cell line Lu1205 which express the mutant kinaseBRAFV600E, and Vemurafenib was employed as positive controlof 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<0.05). In addition, compound 10Calso reduce cell viability (p<0.001). Taking together, these resultsallowed us to identify the compound 10C as a new potential BRAFithat reduce ERK phosphorylation and cell viability. Moreover, thiscompound can be modified in order to design new chemical structureswith improved activity.