KLHL21 Inhibitors

KLHL21 Inhibitors encompass a range of chemical compounds that target the ubiquitination pathway, which is critical for protein turnover and regulation. Proteasome inhibitors such as MG-132 and Bortezomib impede the degradation of ubiquitinated proteins, resulting in the accumulation of KLHL21's substrates and a consequential indirect inhibition of KLHL21's role in the ubiquitin-proteasome system. Similarly, MLN 4924 (Pevonedistat) targets upstream processes by inhibiting the NEDD8-activating enzyme, essential for the activation of Cullin 3, a core component of the E3 ubiquitin ligase complex involving KLHL21. Curcumin and Chloroquine further contribute to the inhibition of KLHL21 by disrupting protein-protein interactions within the E3 ligase complex and by impeding autophagic degradation of ubiquitinated proteins, respectively, leading to a decrease in KLHL21's functional activity.

In addition to these, compounds like Thalidomide, Lenalidomide, and Pomalidomide indirectly inhibit KLHL21 by potentially affecting the assembly and function of E3 ubiquitin ligase complexes through their interaction with cereblon, a substrate receptor for a related E3 ligase. The ubiquitination process is also targeted by MLN7243, an E1 enzyme inhibitor, along with PYR-41, which by the same mechanism, diminishes KLHL21's ability to ubiquitinate substrates. Auranofin, with its impact on redox regulation, may alter the functional state of proteins within the E3 ligase complex, indirectly inhibiting KLHL21. Finally, MLN8237 (Alisertib), an inhibitor of Aurora kinase A, can also attenuate KLHL21 activity by modifying the phosphorylation status of potential KLHL21 substrates, highlighting the intricate interplay between phosphorylation and ubiquitination pathways in regulating protein stability. Together, these KLHL21 inhibitors collectively impede the ubiquitin-proteasome system by various mechanisms, emphasizing the complex regulation of protein degradation processes.