USP37 Inhibitors

Chemical inhibitors of USP37 employ a variety of mechanisms to impede its deubiquitinating activity. Ubiquitin Aldehyde is a potent molecule that engages directly with the active site of USP37, blocking its ability to remove ubiquitin chains from substrates. This direct inhibition ensures that ubiquitin remains attached to proteins, thus preventing the normal recycling process of ubiquitin and accumulation of polyubiquitinated proteins. Similarly, PR-619 and b-AP15 function by binding to the active site of not only USP37 but also other deubiquitinating enzymes. PR-619 is a broad-spectrum inhibitor that escalates the levels of polyubiquitinated proteins, leading to a cellular environment where deubiquitination is broadly hampered, including the activity of USP37. On the other hand, b-AP15 specifically targets USP14 and UCHL5, which are associated with the proteasome, and by doing so, can indirectly affect USP37's function by altering the ubiquitin-proteasome system dynamics, leading to a possible indirect inhibition of USP37.

In addition to these direct and indirect inhibitors, several other compounds target USP37's activity circuitously through the inhibition of related deubiquitinating enzymes. For instance, IU1 specifically inhibits USP14, which could lead to the indirect suppression of USP37 activity by causing a compensatory increase in overall deubiquitinating activity, possibly resulting in a competitive environment for USP37's substrates. HBX 41108, P22077, and HBX 19818 are selective for USP7, and their inhibition of this enzyme can indirectly limit USP37 by disturbing the cellular deubiquitination equilibrium. Furthermore, LDN-57444 and ML323 target UCHL1 and USP1-UAF1, respectively, which can create a ripple effect leading to the modulation of USP37's activity. The disruption or alteration in the ubiquitin signaling caused by these inhibitors can indirectly influence the functional capacity of USP37 within the cellular context.