RNF145 Inhibitors

RNF145 inhibitors work through a variety of biochemical mechanisms that all converge on the common pathway of ubiquitination, a process crucial for protein turnover and cellular regulation. Inhibition of the proteasome with compounds that bind to its active sites leads to an accumulation of ubiquitinated proteins, which can indirectly affect the function of RNF145 by overwhelming the proteolytic system it relies on. By inhibiting the proteasome, these compounds effectively prevent the degradation of proteins that RNF145 has marked for turnover, thereby reducing the efficacy of RNF145's role in cellular protein homeostasis. This is exemplified by peptide aldehydes and boronic acid derivatives, which interfere with the proteasome's ability to recognize and process ubiquitinated substrates, leading to a backlog that indirectly limits RNF145's function.

Additionally, inhibitors that target the upstream processes of ubiquitination, such as those affecting the neddylation of cullin proteins or the ubiquitin-activating enzyme E1, can indirectly inhibit RNF145 by disrupting the ubiquitin-proteasome pathway. The neddylation process is integral to the function of cullin-RING ubiquitin ligases, to which RNF145 may contribute, and by impeding this process, the overall ubiquitination activity can be reduced. Similarly, by inhibiting the initial steps of ubiquitin activation and conjugation to target proteins, these compounds can decrease the functional activity of RNF145 by preventing the tagging of proteins for degradation. Deubiquitinase inhibitors further balance the ubiquitination equilibrium by preventing the removal of ubiquitin chains, which could indirectly lead to the inhibition of RNF145's activity by stabilizing its substrates against proteasomal degradation.