NEDL2 Inhibitors

NEDD8-activating enzyme (NAE) and disrupt the process of neddylation. Neddylation is a post-translational modification critical for the regulation of protein degradation within cells. NEDD8, a ubiquitin-like protein, is covalently attached to cullin proteins in the Cullin-RING E3 Ligases (CRLs) complex through the enzymatic action of NAE. This neddylation process activates CRLs, which are responsible for tagging various proteins for ubiquitination and subsequent proteasomal degradation. The significance of CRLs in controlling protein homeostasis and regulating numerous cellular processes, including cell cycle progression, transcription, and apoptosis, underscores the importance of neddylation as a key regulatory mechanism.

NEDL2 inhibitors, such as MLN4924 (Pevonedistat), TAK-243, and various analogs, work by selectively binding to NAE and inhibiting the activation of NEDD8. By interfering with the neddylation process, these inhibitors disrupt the functionality of CRLs, leading to the stabilization of CRL substrate proteins. Consequently, this inhibition results in the altered turnover of key regulatory proteins involved in various cellular pathways. NEDL2 inhibitors offer valuable tools for researchers to probe the intricacies of neddylation and CRL-mediated protein degradation, shedding light on the roles of specific proteins and pathways in normal cellular physiology and disease. Their utility extends beyond potential applications, as they serve as crucial probes for elucidating the fundamental biology of protein regulation and degradation mechanisms within the cell. Researchers continue to explore the intricacies of NEDL2 inhibitors and their impact on cellular processes, providing valuable insights into the molecular machinery governing protein homeostasis and cellular function.