The ERK pathway is responsible for cellular growth, proliferation and differentiation. Dysregulation of which has been implicated in neurodegenerative disease and tumorigenesis. The two most frequently mutated genes in the pathway correspond to RAS and BRAF, with BRAF being mutated in over 50% of all melanomas. This has led to a great effort in drugging Braf and its mutants (V600E). Current FDA approved BRAF inhibitors suffer from paradoxical activation due to the inability to bind to both protomers of BRAF dimers. Thus, a detailed understanding of BRAF dimerization could lead to the discovery of more effective therapies. Here, we use molecular dynamics to study the conformational dynamics of the apo- and holo-BRAFWT in complex with belvarafenib, an inhibitor which binds both protomers of the dimer and stabilizes the αC-helix in an “in” position. Our data elucidated the interplay between inhibitor binding, dynamics of the αC helix, and dimerization of BRAF. We hope the findings can provide insights for designing more efficacious inhibitors.

How Belvarafenib attenuates the conformational dynamics of BRAF

ACS Spring 2022

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