RAF Inhibitors: Quantifying Drug-Target Occupancy at Active RAS-RAF Complexes in Live Cells

Mitogen-activated protein kinases (MAPKs) are a large family of proteins that regulate diverse cellular functions in eukaryotes, including gene expression, proliferation, differentiation and apoptosis (1). MAPK signaling pathways typically include three sequentially activated kinases, and these pathways are triggered in response to extracellular stimuli, such as cytokines, mitogens, growth factors and oxidative stress (1). Ultimately, the signal is transmitted to the nucleus, with the activation of a specific transcription factor that modulates the expression of one or more genes.

Among MAPK pathways, the RAS-RAF-MEK-ERK signaling pathway has been studied extensively. Mutations in RAS family proteins and resultant dysregulation of the signaling pathway are implicated in a variety of cancers. Therefore, this pathway is a popular target for anticancer drug development.

An overview of the RAS-RAF-MEK-ERK signaling pathway.
Continue reading “RAF Inhibitors: Quantifying Drug-Target Occupancy at Active RAS-RAF Complexes in Live Cells”

Study Reveals New Strategies for Targeting “Undruggable” KRAS Mutants

NanoBRET assays can be used to understand the behavior of drugs targeting KRAS mutants

A new study published in Nature Chemical Biology shows that the most commonly mutated protein in cancer might not be as “undruggable” as previously believed. Promega R&D scientists collaborated with the research group led by Kevan Shokat at the University of California – San Francisco to develop strategies for targeting mutants of KRAS that have evaded previous drug discovery efforts. Their paper opens new possibilities for developing small molecule inhibitors against KRAS(G12D) and other clinically significant mutants.

Continue reading “Study Reveals New Strategies for Targeting “Undruggable” KRAS Mutants”