Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors

Abstract

We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

“…Further exploring the contribution of HECT‐type E3s in autophagy regulation will implement our understanding of the autophagic process. Few inhibitors of the HECT enzymes have been reported to display cytotoxic activities against cancer cells or to increase the response of tumor cells to conventional therapies (Rossi et al ., 2014; Watt et al ., ; Lee et al ., ). It would be of clinical interest to assess whether these compounds function, at least in part, by interfering with the autophagic pathway.…”

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

“…For example, WWP1 has been found amplified in numerous tumors, while downregulation of WWP1 attenuates leukemic cell growth . Similar to WWP1, a small‐molecule inhibitor of WWP2 has been investigated and might have an anti‐tumor function . Furthermore, enhancing or disruption of the protein‐protein interactions between WW domain‐containing E3 and its substrate is a novel strategy to treat cancers and diseases.…”

Small molecules that target the ubiquitin system

“…High-throughput screening of small molecule libraries [65] has yielded many compounds (see Table 2, structures 5-9) that show promise as potentially therapeutically relevant WWP2 E3 ligase inhibitors (IC 50 values are in the low mM range). The sites of interaction between inhibitor and target have been determined by NMR, which may facilitate the process of refining these WWP2 inhibitors.…”