Neddylation has emerged as a major regulatory pathway with a critical role, among others, in cell cycle progression and survival.

[12] Thus, APPBP1 carries out an initiating step that controls major regulatory pathways in the cell.

[13] The interface between NEDD8 and APPBP1 involves the helix and subsequent loop in NEDD8 and a sub-domain comprising APPBP1’s residues 178–280 that serves as a wall for the broad, deep groove in the APPBP1-UBA3 structure.

[14] NEDD8 interacts with an adenylation pocket of the UBA3 part of the heterodimeric NAE to form covalently linked NEDD8-AMP.

The first step in this pathway depends on the Ku70/Ku80 heterodimer that forms a highly stable ring structure encircling DNA ends.

[17] But the Ku heterodimer needs to be removed when NHEJ is completed, or it can block transcription or replication.

If activation of NEDD8 is inhibited by Pevonedistat, cancer cells will then have an additional induced deficiency of NER or NHEJ.

In a phase 1 trial of Pevonedistat to determine dosing in patients with AML and myelodysplastic syndromes "modest clinical activity was observed".

[20] More recently, in 2016, Pevonedistat has shown a significant therapeutic effect in three further Phase I clinical cancer trials.

These include Pevonedistat trials against relapsed/refractory multiple myeloma or lymphoma,[21] metastatic melanoma,[22] and advanced solid tumors.