Hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols, two new series of BRAF inhibitors. A theoretical and experimental study

CAMPOS, LUDMILA E.; GARIBOTTO, FRANCISCO; ANGELINA, EMILIO; KOS, JIRI; GONEC, TOMAS; MARVANOVA, PAVLINA; VETTORAZZI, MARCELA; ORAVEC, MICHAL; JENDRZEJEWSKA, IZABELA; JAMPILEK, JOSEF; ALVAREZ, SERGIO E.; ENRIZ, RICARDO D.

BIOORGANIC CHEMISTRY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2020 vol. 103

0045-2068

The oncogenic mutated kinase BRAFV600E is an attractive molecular target because it is expressed in severalhuman cancers, including melanoma. To present, only three BRAF small inhibitors are approved by the FDA forthe treatment of patients with metastatic melanoma: Vemurafenib, Dabrafenib and Encorafenib. Although manyprotocol treatments have been probed in clinical trials, BRAF inhibition has a limited effectiveness becausepatients invariably develop resistance and secondary toxic effects associated with the therapy. These limitationshighlight the importance of designing new and better inhibitors with different structures that could establishdifferent interactions in the active site of the enzyme and therefore decrease resistance progress.Considering the data from our previous report, here we studied two series of derivatives of structural scaffoldsas potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our re­sults indicate that structural analogues of substituted piperazinylpropandiols do not show significantly betteractivities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantlyinhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanomacells. In order to better understand these experimental results, we carried out a molecular modeling study usingdifferent combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM)calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the differentmolecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, wefound that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues, byestablishing additional interactions with the DFG-loop at the BRAF-active site. On the bases of these results wesynthesized and tested a new series of hydroxynaphthalenecarboxamides bi-substituted. Remarkably, all thesecompounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural informationreported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold.