The MAPK/ERK cell signaling pathway is responsible for regulation of cell proliferation and differentiation. Frequently in cancer, members of this pathway become mutated, thus dysregulating controls and allowing for continual cell proliferation and tumorigenesis. In cases of metastatic melanoma, the RAF isoform, BRAF, has a high mutation frequency, specifically for the V600E point mutation. In the past decade, Type I kinase inhibitors have been developed for this indication, but therapy was met with drug resistance driven by the combination of oncogenic RAS and paradoxical activation of BRAF-wt, through drug induced dimerization. Through mutagenesis studies on BRAF, the Brummer group discovered that an intact BRAF dimer interface (DIF) was required for drug-induced paradoxical activation. Initial studies using a linear peptide of the BRAF DIF sequence demonstrated dose-dependent inhibition of downstream MEK/ERK activation under paradoxical activation conditions, exhibiting Kd = 3.84 µM in a direct binding assay. This sequence was cyclized to maintain the reverse-β-turn bioactive conformation, leading to a 63-fold increase in binding affinity due to the decreased entropic cost of binding. The sequence has been further optimized for drug-likeness through truncation and the use of the REPLACE strategy, the iterative method of replacing peptidic sequences with small molecule fragments. The exocyclic sequences of the peptide were replaced with non-peptidic capping groups which resulted in a macrocycle with a 225-fold increase in binding affinity relative to the initial linear peptide. This research has led to the design of Type IV BRAF kinase inhibitors which have the therapeutic potential to prevent drug-induced paradoxical activation in melanoma patients treated with Type I kinase inhibitors.

Design of Type IV macrocyclic BRAF dimerization inhibitors for the treatment of metastatic melanoma

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.