Highly activated neddylation pathway in lung cancer and chemical targeted intervention

<p indent="0mm">Protein neddylation is one type of post-translational modifications in which NEDD8 is attached covalently to a lysine residue of a substrate. Neddylation is catalyzed by E1 activation enzyme (NAE), E2 conjugating enzymes, and E3 ligases. Cullin family members are the physiological substrates of neddylation, and cullin neddylation activates cullin-RING ligases (CRLs), which then promote ubiquitylation and proteasome degradation of many key signal proteins, thus regulating many important biological process. Accumulated data showed that neddylation pathway is highly activated in human lung cancer with positive correlation to poor survival of lung cancer patients. Activated neddylation pathway promotes the proliferation and survival of lung cancer cells, and accelerates lung tumorigenesis. Thus, targeting neddylation has become an attractive approach for the discovery and development of anti-lung cancer therapy. In this review, we first introduce neddylation process, its biochemical properties, and its alterations via bioinformatics analysis, and its known tumor promoting functions in lung cancer. We then list few advanced methodologies/techniques for the discovery of small molecule inhibitors of neddylation enzymes, followed by a comprehensive summary of all known inhibitors of neddylation enzymes. We end the review with brief summary and proposed future perspectives. The goal is to provide a most updated and comprehensive information to the readers of interest, and to draw more scientists to join the effort in the discovery of neddylation inhibitors for anti-cancer therapy.