USP6 Inhibitors

Chemical inhibitors of USP6 offer diverse mechanisms of action to impede its deubiquitinase activity. WP1130 targets USP6 by binding and obstructing its deubiquitinase function, thereby preventing the cleavage of ubiquitin from its protein substrates, which is crucial for their stability and signaling pathways. Similarly, P22077 takes a covalent approach to modify the active site of USP6, leading to a disruption in its activity and resulting in an accumulation of ubiquitin-protein conjugates within the cell. This accumulation can affect the normal turnover and function of proteins regulated by USP6. NSC632839 employs a non-covalent binding strategy to inhibit USP6, thereby interfering with the enzyme's ability to process ubiquitin-protein conjugates. LDN-57444, on the other hand, irreversibly binds to the active site of USP6, causing a sustained inhibition and affecting the enzyme's role in protein turnover.

Moreover, HBX 41108 acts as an inhibitor by directly binding to the active site of USP6 and altering its catalytic function. In a different approach, IU1, although a selective inhibitor of USP14, can indirectly impact USP6 activity by altering the overall dynamics of the ubiquitin-proteasome system, which can inadvertently affect USP6's functional status in the cell. ML323 targets the USP1-UAF1 complex, which can have downstream effects on USP6 activity due to the interconnected nature of ubiquitination pathways. Similarly, b-AP15 affects USP6 indirectly by inhibiting USP14 and UCHL5, both of which are associated with the proteasome, leading to disruptions in ubiquitin-dependent degradation pathways where USP6 is involved. HBX 19818 specifically targets USP7, another deubiquitinase, which can have secondary effects on USP6's activity due to the overlapping nature of substrate processing among deubiquitinases. VLX1570 is also known to exert its effects on USP6 indirectly by targeting proteasome-associated deubiquitinases, which in turn affects the ubiquitinated protein load that USP6 may regulate. Lastly, RA-9 and SJB3-019A are direct inhibitors of USP6, with RA-9 impeding the substrate interaction of the enzyme, and SJB3-019A covalently modifying the active site cysteine residue of USP6, both leading to a significant decrease in USP6 deubiquitinase activity.