Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques

CAMPOS, LUDMILA E.; GARIBOTTO, FRANCISCO M.; ANGELINA, EMILIO; KOS, JIRI; TOMASIC, TIHOMIR; ZIDAR, NACE; KIKELJ, DANIJEL; GONEC, TOMAS; MARVANOVA, PAVLINA; MOKRY, PETR; JAMPILEK, JOSEF; ALVAREZ, SERGIO E.; ENRIZ, RICARDO D.

BIOORGANIC CHEMISTRY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2019 vol. 91

0045-2068

The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanomapatients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date,Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastaticmelanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressiveand lethal disease, making imperative the development of new therapeutic options. The main objective of thiswork was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Ourstudy was carried out in different stages; in the first step we performed a virtual screening that allowed us toidentify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of thenovel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understandinteractions at the molecular level that stabilize the formation of the different molecular complexes.Our theoretical and experimental study allowed the identification of four new structural scaffolds, whichcould be used as starting structures for the design and development of new inhibitors of BRAF. Our experimentaldata indicate that the most active compounds reduced significantly ERK½ phosphorylation, a measure of BRAFinhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substitutedhydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanolsand substituted piperazinylpropandiols as initial structures for the development of new inhibitorsfor BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecularinteractions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of thedifferent molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.