Multi-Kinase Inhibition and MYC Depletion
Kinase inhibition of CDK9—in particular—offers an exciting therapeutic opportunity, because CDK9 inhibition results in the depletion of the key oncogenic protein MYC.
MYC is one of the first discovered oncogenes and is overexpressed in many cancers, including 80% of high-grade gliomas.1
An overexpression of MYC is associated with tumorigenesis, playing a key role in cellular proliferation, and with abnormal glucose and glutamine metabolism.2 By reducing MYC, oncogenic activity of metabolite 2-hydroxyglutarate is interrupted and tumorigenic activities of high-grade gliomas are reduced.3-5
Tumor Growth Is Blunted With Decreased Levels of 2-Hydroxyglutarate
MYC depletion stymies oncogenic pathways and decreases metabolic activity,
reducing the activity of 2-hydroxyglutarate, an oncometabolite produced in
Multi-Kinase Inhibition Increases Cell Death via MCL-1 Depletion
MCL-1 is a member of the BCL-2 family of antiapoptotic proteins, which interfere with the process of programmed cell death that can occur if aberrant activity in a cancer cell is detected. This has been demonstrated to be an effective anticancer approach, given that cancer cells are known to be more prone to apoptosis than normal cells.8
BCL-2 antiapoptotic proteins have become established therapeutic targets, with the BCL-2 inhibitor venetoclax attaining standard-of-care status in both chronic lymphocytic leukemia and acute myeloid leukemia.