Discovery of new covalent inhibitors of monoacylglycerol lipase with the nitrile warhead via SCARdock

Monoacylglycerol Lipase (MAGL) is an important Enzyme for endocannabinoid metabolism by converting 2-arachidonoylglycerol (2-AG) into glycerol and free fatty acids. Modulation of the endocannabinoid system by inhibiting MAGL provides a promising therapeutic strategy for various diseases. In this work, we identified five new MAGL inhibitors with the nitrile group by high-throughput screening using SCARdock, a protocol presented by us for covalent drug discovery. Compounds ZQ-4, ZQ-5, ZQ-6, and ZQ-7 inhibit MAGL activity in a time-dependent and concentration-dependent manner. Furthermore, ZQ-7 was confirmed to covalently bind with the residue Ser132 of MAGL. The nitrile group is a new covalent warhead that has never been used in previous covalent MAGL inhibitors. At last, the efficacy of the new MAGL inhibitors on inhibiting breast Cancer cells was investigated. Significantly increased 2-AG levels were detected in MDA-MB-231 cells treated with MAGL Inhibitor ZQ-5, ZQ-6, ZQ-7, ZQ-19, and KML29, a previously identified MAGL covalent inhibitor. Moreover, these MAGL inhibitors inhibited the proliferation and migration of MDA-MB-231 cells. This work expands the application of SCARdock and provides meaningful clues for developing better MAGL inhibitors.

Breast cancer; Covalent inhibitor; MAGL; SCARdock.