Can VHL E3 ligase be more active in protein degradation in cancer tissue?

Hypoxia is common in most solid tumors, resulting from an insufficient vascular oxygen supply that fails to meet the demands of rapidly proliferating cancer cells. This hypoxic tumor microenvironment can reduce the effectiveness of treatments such as chemotherapy or immunotherapy.

Recently, a publication on the stability of HIF-1α through citrullination modulation caught my attention - link, particularly Figure 4E. It illustrates how citrullination of HIF-1α can block the binding to VHL, preventing the degradation of HIF-1α and thereby promoting tumor progression

Theoretically, this mechanism could be leveraged to our advantage when designing PROTACs for cancer cells with elevated expression levels of proteins involved in this pathway, such as in hepatocellular carcinoma tumors.

Blocking the interaction between VHL and HIF-1α would likely increase the concentration of 'free' VHL E3 ligase, which is normally complexed with HIF-1α. As a result, incorporating a VHL warhead into PROTACs could enhance the degradation rate of the target protein.

#TPD #Targeted_Protein_Degradation #VHL