Expanding the Ligandable Chemical Space of OTUB1 through Discovery of a Four-Membered-Ring Recruiter Chemotype

Deubiquitinase-targeting chimeras, or DUBTACs, have shown potential for targeted protein stabilization, although their wider use is constrained by the limited number of ligandable deubiquitinase recruiters. In a recent study, researchers identified a novel four-membered-ring OTUB1 recruiter chemotype that could potentially overcome this limitation.

Through extensive structure-activity relationship studies, they discovered compound 21 (MS2159) as a highly effective and selective covalent OTUB1 ligand. Biochemical and intact protein mass spectrometric tests revealed that MS2159 specifically targets the non-catalytic C23 residue of OTUB1 while remaining inactive on other proteins, and importantly, it does not impair OTUB1's deubiquitinase activity.

Furthermore, when MS2159 was linked to the CFTR ligand lumacaftor, it produced compound 25 (MS2134), which successfully stabilized the {Delta}F508-CFTR variant. These findings not only introduce a new OTUB1 recruiter scaffold but also broaden the ligandable chemical space of OTUB1, paving the way for the development of next-generation DUBTACs.