KLHL28 Inhibitors

KLHL28, a protein implicated in the ubiquitination of substrates for proteasomal degradation, is regulated through its E3 ubiquitin ligase activity. Compounds that target the ubiquitin-proteasome system can, therefore, indirectly inhibit the functional activity of KLHL28. By stabilizing the proteins that KLHL28 marks for degradation, proteasome inhibitors essentially counteract KLHL28's role in the cell. These compounds achieve this by binding to the proteasome and disrupting its proteolytic functions, leading to an accumulation of KLHL28-ubiquitinated proteins. The inhibition process is further enhanced by agents that impede the upstream elements of the ubiquitination cascade, including those affecting the NEDD8-activating enzyme, which is essential for the full activation of the E3 ligase activity of KLHL28. In addition, the ubiquitin-activating enzyme E1 is another target for compounds which, by their inhibitory action, can result in a ubiquitin-depleted environment, thus limiting the ubiquitination capacity of KLHL28. Further indirect inhibition of KLHL28's activity is achieved through the modulation of proteasomal degradation pathways. Compounds that inhibit the proteasome's chymotrypsin-like activity particularly affect the turnover of proteins that KLHL28 targets. The resulting proteostasis imbalance due to the inhibition of proteolysis signifies an indirect blockage of KLHL28's function. This modulation of protein degradation pathways, which maintains higher levels of proteins that would otherwise be degraded, essentially serves as an inhibitory mechanism for KLHL28's biological role.