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Rational design and development of new chemical entity as potentially BRAF V600E inhibitor to treat melanoma


The proposal comprises the synthesis of a novel inhibitor of protein B-RAF V600E to treat melanoma (product) and the evaluation in vitro and in vivo of its pharmacological activity. Melanona represents only 4% of the types of skin cancer, but it is considered a highly aggressive disease due to its invasiveness and ability to develop metastasis. The World Health Organization has estimated that skin cancer causes 66,000 deaths per year worldwide and 80 % are attributed to melanomas. The treatment of metastatic melanoma especially with inhibitors of the mutant protein kinase serine/threonine (B-RAF V600E) from MAPK pathway has shown promising clinical results. The most common B-RAF gene mutation found in certain types of human cancer is the replacement of the amino acid residue valine (Val or V) at position 600 by glutamic acid (Glu or E). Considering the development of more selective and less toxic new molecules, the computer-assisted drug design (CADD) strategies can play important role. Herein, he strategy called structure-based drug design (SBDD) was employed. The new inhibitor B-RAF V600E, named BRAF_NOX1, was designed based on the three-dimensional (3D) structure of the target and a benzofuraxan derivative, BFD-22, was used as a lead compound. BRAF_NOX1 presents molecular modifications to better occupy/accommodate into the B-RAF V600E site in order to establish interactions with residues of ATP binding site. Organic synthesis and biological evaluation, in vitro and in vivo (proofs of concept), are the main activities in this proposal. (AU)