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

Lugar: Amsterdam; Año: 2019 vol. 91

0045-2068

p { margin-bottom: 0.1in; line-height: 120%; }Theidentification of the V600E activating mutation in the protein kinaseBRAF in around 50% of melanoma patients has driven the developmentof highly potent small inhibitors (BRAFi) of the mutated protein. Todate, Dabrafenib and Vemurafenib, two specific BRAFi, have beenclinically approved for the treatment of metastatic melanoma.Unfortunately, after the initial response, tumors become resistantand patients develop a progressive and lethal disease, makingimperative the development of new therapeutic options. The mainobjective of this work was to find new BRAF inhibitors withdifferent structural scaffolds than those of the known inhibitors.Our study was carried out in different stages; in the first step weperformed a virtual screening that allowed us to identify potentialnew inhibitors. In the second step, we synthesized and tested theinhibitory activity of the novel compounds founded. Finally, weconducted a molecular modelling study that allowed us to understandinteractions at the molecular level that stabilize the formation ofthe different molecular complexes. Ourtheoretical and experimental study allowed the identification of fournew structural scaffolds, which could be used as starting structuresfor the design and development of new inhibitors of BRAF. Ourexperimental data indicate that the most active compounds reducedsignificantly ERK1⁄2 phosphorylation, a measure of BRAFinhibition, and cell viability. Thus, from our theoretical andexperimental results, we propose new substitutedhydroxynaphthalenecarboxamides,N-(hetero)arylpiperazinylhydroxyalkylphenylcarbamates, substitutedpiperazinylethanols and substituted piperazinylpropandiols as initialstructures for the development of new inhibitors for BRAF. Moreover,by performing QTAIM analysis, we are able to describe in detail themolecular interactions that stabilize the different Ligand-Receptorcomplexes. Such analysis indicates which portion of the differentmolecules must be changed in order to obtain an increase in thebinding affinity of these new ligands.