Rad23 Inhibitors

Chemical inhibitors of Rad23 target its association with the proteasome and the ubiquitin-proteasome pathway, where it plays a role in shuttling polyubiquitinated proteins for degradation. MG-132, Lactacystin, Velcade (Bortezomib), Carfilzomib, Epoxomicin, MLN9708 (Ixazomib), Oprozomib, Marizomib, Delanzomib, PI-1840, Salinosporamide A (NPI-0052), and ONX 0914 (PR-957) are all proteasome inhibitors that act to increase the levels of ubiquitinated proteins. This accumulation can saturate Rad23's ubiquitin-binding domains, inhibiting its function. For instance, MG-132 and Lactacystin directly inhibit the proteolytic activity of the proteasome, leading to an increase in Rad23-bound polyubiquitinated proteins, thereby inhibiting Rad23's role in protein turnover. Similarly, Velcade forms a reversible complex with the proteasome, increasing the amount of ubiquitinated proteins, which in turn inhibits Rad23 by overwhelming its binding capacity.

Carfilzomib and Epoxomicin irreversibly inhibit the proteasome, leading to an accumulation of polyubiquitinated proteins, which hinders Rad23's function in shuttling these proteins for degradation. MLN9708, once activated to MLN2238, and Oprozomib bind to and inhibit the proteasome, increasing the ubiquitinated protein load and consequently inhibiting Rad23's role. Marizomib and Delanzomib, through their proteasome inhibitory actions, prevent the normal function of Rad23 in the degradation of ubiquitinated protein substrates. PI-1840, by inhibiting the proteasome, leads to a buildup of ubiquitinated proteins, which saturates Rad23's ubiquitin-associated domains and inhibits its function in the degradation process. Salinosporamide A, through its proteasome inhibition, stops Rad23 from facilitating the degradation of ubiquitinated proteins, resulting in its functional inhibition. Finally, ONX 0914 selectively inhibits the immunoproteasome subunit LMP7, which could lead to an accumulation of ubiquitinated proteins, thus inhibiting Rad23's role in antigen processing and immune responses. Each of these chemicals, by inhibiting the proteasome, indirectly inhibits Rad23's ability to perform its role in protein degradation.