RNF24 Inhibitors

Chemical inhibitors of RNF24 function by targeting various aspects of the ubiquitin-proteasome system, which is integral to the protein's role in cellular processes. Pyrrolidine dithiocarbamate (PDTC) inhibits NF-κB activation, a pathway that RNF24 is involved in. This inhibition could lead to reduced transcription of RNF24 target genes, thereby decreasing RNF24-mediated ubiquitination activity. Proteasome inhibitors such as MG-132, Bortezomib, Epoxomicin, Lactacystin, Clasto-lactacystin β-lactone, Carfilzomib, Oprozomib, Marizomib, Ixazomib, Nelfinavir, and Velcade, have a different approach. These compounds prevent the proteasome from degrading ubiquitin-tagged proteins, which can lead to an accumulation of these proteins within the cell. As a result, RNF24's ubiquitination machinery can become overloaded, which may reduce its efficiency or ability to ubiquitinate additional substrates, thereby functionally inhibiting RNF24.

The role of RNF24 in the ubiquitin-proteasome pathway is crucial for the degradation of proteins, and by extension, the regulation of various cellular functions. The aforementioned chemical inhibitors exert their inhibitory effect by causing an increase in ubiquitinated proteins that are not adequately degraded due to proteasome inhibition. This accumulation can saturate RNF24, and as a result, RNF24's ability to tag new proteins for degradation is compromised. For example, Epoxomicin and Marizomib specifically inhibit the proteasome, leading to an indirect inhibition of RNF24 by blocking the degradation of ubiquitinated proteins. On the other hand, Lactacystin and its clasto- derivative act upon the proteasome, potentially interfering with RNF24's role in the ubiquitin-proteasome system. The selective inhibition of the proteasome's beta5 subunit by Ixazomib represents another strategy by which RNF24 is inhibited, as it prevents the turnover of proteins that RNF24 targets for degradation. Nelfinavir, although primarily an HIV protease inhibitor, also exhibits off-target effects that inhibit the proteasome, leading to a similar functional inhibition of RNF24. These chemical inhibitors collectively demonstrate a range of mechanisms by which the functional activity of RNF24 can be inhibited, focusing primarily on the accumulation of ubiquitinated proteins that would otherwise be substrates for RNF24.