MAGL inhibitors(Lunan Pharmaceutical Group)

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.

Background: Evidence suggests that monoacylglycerol lipase (MAGL) inhibitors can potentially treat HIV symptoms by increasing the concentration of 2-arachidonoylglycerol (2-AG). We examined a selective MAGL inhibitor ABX1431 in the context of neuroHIV. Methods: To assess the effects of ABX1431, we conducted in vitro and in vivo studies. In vitro calcium imaging on frontal cortex neuronal cultures was performed to evaluate the role of ABX1431 (10, 30, 100 nM) on transactivator of transcription (Tat)-induced neuronal hyperexcitability. Following in vitro experiments, in vivo experiments were performed using Tat transgenic male mice. Mice were treated with 4 mg/kg ABX1431 and assessed for antinociception using tail-flick and hot plate assays followed by locomotor activity. After the behavioral experiments, their brains were harvested to quantify endocannabinoids (eCB) and related lipids through mass spectrometry, and cannabinoid type-1 and -2 receptors (CB₁R and CB₂R) were quantified through western blot. Results: In vitro studies revealed that adding Tat directly to the neuronal cultures significantly increased intracellular calcium concentration, which ABX1431 completely reversed at all concentrations. Preincubating the cultures with CB₁R and CB₂R antagonists showed that ABX1431 exhibited its effects partially through CB₁R. In vivo studies demonstrated that acute ABX1431 increased overall total distance traveled and speed of mice regardless of their genotype. Mass spectrometry and western blot analyses revealed differential effects on the eCB system based on Tat expression. The 2-AG levels were significantly upregulated following ABX1431 treatment in the striatum and spinal cord. Arachidonic acid (AA) was also upregulated in the striatum of vehicle-treated Tat(+) mice. No changes were noted in CB₁R expression levels; however, CB₂R levels were increased in ABX1431-treated Tat(-) mice only. Conclusion: Findings indicate that ABX1431 has potential neuroprotective effects in vitro partially mediated through CB₁R. Acute treatment of ABX1431 in vivo shows antinociceptive effects, and seems to alter locomotor activity, with upregulating 2-AG levels in the striatum and spinal cord.