Novel anti-cancer drugs
Over the years, drugs have been developed that can improve cancer patient survival by targeting oncogenic proteins. Emerging evidence, however, suggests that cancer cells have defects in tumour suppressor genes and restoration of their activity might be beneficial. The scope of the EU-funded TARGET-PPIS (Targeting the ubiquitin-proteasome system and ubiquitin-like protein conjugation pathways for non-genotoxic therapy of cancer) project was to develop small-molecule compounds against cancer cells. Their work focused on the ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways, which are integral to protein homeostasis. Using nuclear magnetic resonance and X-ray crystallography, researchers structurally characterised the interaction between the oncogenic E3 ligase Mdm2 and the tumour suppressor p53. Disruption of the Mdm2-p53 axis is emerging as an attractive anti-cancer approach for restoring impaired p53 function. Researchers successfully designed inhibitors that interfered with the Mdm2-p53 interaction at various transient protein states. Testing on patient samples revealed that agents antagonising the Mdm2-p53 interaction induced apoptosis in acute myeloid leukaemia cells. Additionally, they studied the deubiquitinating protease USP2 and identified inhibitors directed to the catalytic domain that interfered with ubiquitin binding. Furthermore, they characterised the interaction of the non-canonical UBL protein Hub1 with the immune checkpoint proteins PD-1 and PD-L1. Targeting the latter with antibodies has emerged as a revolutionary new oncology treatment capable of converting lethal cancers into treatable ones. The structural information provided by TARGET-PPIS is expected to facilitate further antibody development against these two targets. Overall, modulating tumorigenesis through a small-molecule approach offers several unique advantages including the potential to be used in conjunction with other modalities. The TARGET-PPIS deliverables provided fundamental structural information for advancing this approach.
Keywords
Cancer, drugs, protein, degradation, UPS, UBL, Mdm2, p53, USP2, PD-1, -PD-L1
