FBXO36 Inhibitors

Chemical inhibitors of FBXO36 include a series of proteasome inhibitors that obstruct the protein's ability to facilitate the degradation of its substrates. MG132 acts by preventing the proteasomal degradation, leading to the accumulation of proteins that would otherwise be tagged for degradation by FBXO36. This accumulation can saturate the ubiquitin-proteasome system, thereby inhibiting the functional activity of FBXO36 as it is unable to target new proteins effectively. Similarly, Lactacystin targets the proteasome, increasing the levels of FBXO36 substrates within the cell, which could lead to a feedback inhibition of FBXO36's ligase activity. The presence of these undegraded substrates can interfere with FBXO36's ability to bind and ubiquitinate new target proteins. Bortezomib and its analog Velcade, Carfilzomib, Epoxomicin, Ixazomib, Oprozomib, Delanzomib, Marizomib, ONX-0914, and MLN9708 all function as proteasome inhibitors, stabilizing proteins that FBXO36 might target for ubiquitination. These inhibitors lead to an increased concentration of polyubiquitinated proteins within cells, which could inhibit FBXO36's function by overwhelming its E3 ubiquitin ligase activity. By stabilizing these proteins, FBXO36 is indirectly inhibited as it is unable to continue its role in marking proteins for proteasomal degradation. ONX-0914 specifically inhibits the immunoproteasome, which could lead to the inhibition of FBXO36 by preventing the degradation of immune signaling proteins that are potential substrates of FBXO36. This increased level of substrates can lead to a functional inhibition of FBXO36, as the E3 ligase is rendered incapable of effectively tagging additional proteins for degradation due to the high substrate concentration already present.