Fig. 1.

Proposed cytotoxic mechanisms of NEDDylaton inhibition in human malignancies. With inhibition of NEDD8 conjugation pathway, certain critical CRL substrates will accumulate and will lead to cancer cell death. Major proteins identified to induce cell death include cell cycle licensing factor Cdt1; cyclin-dependent kinase inhibitor p21; a negative regulator of entry into mitosis WEE1; mTOR pathway inhibitor Deptor 1; NFκB pathway inhibitor IκB. Due to distinct cellular context, different mechanisms were proposed in different cancer cell lines tested with MLN4924