FBXO16 Inhibitors

Chemical inhibitors of FBXO16 can impede its function in the ubiquitin-proteasome system (UPS), a cellular pathway responsible for degrading misfolded, damaged, or regulatory proteins. Proteasome inhibitors such as MG132, Bortezomib, Epoxomicin, Lactacystin, MLN2238 (Ixazomib), Carfilzomib, Delanzomib, Marizomib, Oprozomib, Withaferin A, and Celastrol disrupt this protein degradation machinery. FBXO16, as part of an E3 ubiquitin ligase complex, tags proteins with ubiquitin molecules, signaling them for degradation by the proteasome. By inhibiting the proteasome, these chemicals can cause an accumulation of proteins that FBXO16 would typically mark for degradation. This accumulation can saturate the UPS and impair the turnover of proteins, leading to a functional inhibition of FBXO16. The buildup of ubiquitinated proteins due to proteasome inhibition can also feedback inhibit the activity of FBXO16 by hindering its access to substrates or by altering its regulatory state. Furthermore, PR-619, a broad-spectrum deubiquitinase inhibitor, can also modulate the activity of FBXO16. Deubiquitinases are enzymes that remove ubiquitin molecules from proteins, often rescuing them from degradation. By inhibiting deubiquitinases, PR-619 can lead to an abnormal accumulation of ubiquitinated proteins. This aberrant ubiquitination can, in turn, obstruct the normal function of FBXO16 by either directly altering its substrates or by disrupting the finely tuned balance of ubiquitination and deubiquitination that FBXO16 relies on to execute its role in protein turnover. Consequently, the inhibition of deubiquitinases can indirectly inhibit the function of FBXO16 by preventing it from tagging proteins for degradation effectively, thereby functionally inhibiting the protein's role in the UPS.