Covalent Inhibitors of Monoacylglycerol Lipase Induce Conformational Changes and Proteasomal Degradation

Monoacylglycerol lipase (MGLL) is a key serine hydrolase that regulates 2-arachidonoylglycerol (2-AG) and eicosanoid signaling. Inhibition of MGLL blocks the conversion of 2-AG into arachidonic acid (AA) with broad therapeutic implications in inflammation, cancer, and viral infection. Carbamate/urea inhibitors such as MJN110, JZL184, and SAR629 are widely used to irreversibly inhibit MGLL through covalent modification of the catalytic serine residue. Here, we demonstrate that this inhibitor class also induces proteasome-dependent degradation of MGLL, functioning as monovalent degraders. We show that loss of MGLL following covalent inhibitor treatment is dependent on the 26S proteasome, while detailed simulations of MGLL dynamics following inhibitor binding suggest that these inhibitors do not destabilize their protein target but instead induce conformational changes that likely facilitate polyubiquitination by exposing two lysine residues. Taken together, these findings establish carbamate/urea inhibitors as dual functional molecules with the propensity to both covalently inhibit their target and act as structural degraders, potentially functioning as monovalent molecular glues, highlighting the need to evaluate the degradation potential alongside inhibitory potency in future screening and drug discovery.