Targeting cullin neddylation for cancer and fibrotic diseases

Abstract

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.

Application of 3D, 4D, 5D, and 6D bioprinting in cancer research: what does the future look like?

“…131 For instance, human colon cancer spheroids' resistance to ionizing radiation was boosted by increased cell compaction. 132 Along with the aforementioned mechanisms, oxygen deficiency in the spheroids may contribute to radio-resistance since it seems to be necessary to fix DNA damage brought on by radiation. 133,134…”

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…The common types of PTMs include ubiquitination ( 13 ), acetylation ( 14 , 15 ), phosphorylation ( 16 ), methylation ( 17 ), glycosylation ( 18 , 19 ), SUMOylation ( 20 ), prenylation ( 21 ), GlcNAcylation ( 18 ), succinylation ( 22 ), palmitoylation ( 23 ), and neddylation ( 24 , 25 ). Ubiquitination is one common type of PTMs, in which a target protein is added a small protein called ubiquitin or multiple ubiquitins, leading to protein degradation by the proteasome ( 26 ).…”

Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways

“…The TME is a complex milieu that encapsulates tumor cells and is defined by intricate interactions between neoplastic cells and the various TME constituents [ 53 ]. Recent studies have highlighted neddylation’s pivotal role in shaping the TME, influencing malignant cells, immune cells, vascular networks, the epithelial-to-mesenchymal transition (EMT) and the ECM [ 54 , 55 ]. Neddylation regulation within the TME has profound implications for tumor prognosis [ 56 ].…”