OTUB2 Inhibitors

OTUB2 (Ovarian Tumor Domain-Containing Ubiquitin Aldehyde Binding Protein 2) inhibitors primarily operate through direct inhibition of OTUB2's deubiquitinating activity or by altering the ubiquitin-proteasome system in which OTUB2 is a participant. PR-619 and ML364 directly inhibit OTUB2's isopeptidase activity. HBX 41,108, on the other hand, disrupts OTUB2's ability to interact with ubiquitin, therefore diminishing its deubiquitinating efficiency. NSC632839, b-AP15, and WP1130 inhibit deubiquitinating enzymes more broadly but have been shown to effectively disrupt the cleavage of ubiquitin moieties by OTUB2. Such inhibition of OTUB2's interaction with ubiquitin hinders its enzymatic activity and, subsequently, its cellular roles.

Further compounds like LDN-57444 inhibit UCHL1, affecting the availability of ubiquitin and indirectly influencing OTUB2's ability to interact with its substrate. In addition to ubiquitin interaction, OTUB2 also plays roles in endosomal sorting and DNA damage repair. Chloroquine inhibits endosomal acidification, thus impairing OTUB2's function in endosomal sorting, while Mitoxantrone affects OTUB2's role in DNA repair. Spautin-1 disrupts autophagy, affecting the degradation of proteins regulated by OTUB2. Eeyarestatin I operates by inhibiting the ERAD system, reducing the ubiquitinated protein supply to OTUB2, thereby limiting its function. Finally, Curcumin affects OTUB2's role in NF-kB activation by being an NF-kB inhibitor. Therefore, OTUB2 inhibitors can be categorized based on their mechanism of action, whether direct or indirect, in affecting OTUB2's enzymatic activity or its downstream functions.