Optimization of a Benzoylpiperidine Class Identifies a Highly Potent and Selective Reversible Monoacylglycerol Lipase (MAGL) Inhibitor

Abstract

Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2arachidonoylglycerol and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50 = 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Concerning pathomechanism of MAGL, formation of protumorigenic lipid signals rather than lowering eCBs' levels causes procancerogenic effects [280]. Recent research is focused on highly selective reversible MAGL inhibitors with anticancer properties [281]. For instance, JZL184 was reported to reduce cancer cells growth, induce apoptosis, and prevent invasion in vitro [279,282] as well as suppress osteolytic bone metastasis and alleviate cachexia and bone mass loss in rodents (8-16 mg/kg) [283].…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…140 The carbamate derivative CAY10499 is a covalent irreversible inhibitor of MAGL, with an IC 50 of 134 nM for hMAGL. 141 However, CAY10499 is not a selective inhibitor of MAGL, as it is also active against FAAH. 140 The authors suggested that the active moiety of CAY10499 is the 5-methoxy-1,3,4-oxadiazol-2(3H)-one moiety and not the carbamate.…”

“…Further studies showed that CAY10499 is active against five tumor cell lines: human breast (MDA-MB-231), colorectal (HCT116), and ovarian (OVSAHO, CAOV3, COV318, OVCAR3, and SKOV3) cancer cell lines. 141,142 The first selective and in vivo active, irreversible inhibitor of MAGL was synthesized in 2009 by Long et al 143 The JZL184 (30, Figure 5) is a piperidine carbamate compound that binds covalently and irreversibly by carbamylating a serine residue in the active site of MAGL. It has an IC 50 of 6 nM for hMAGL.…”

Application of MM-PBSA Methods in Virtual Screening

“…In association to robust docking studies and sufficiently long molecular dynamics (MD) simulations, MM-PBSA and similar approaches can be employed in thorough pose prediction studies aimed at identifying the most reliable disposition of an active compound into the binding site of its target, when no information about its bioactive conformation is known [28]. Moreover, MM-PBSA evaluations can be used for better rationalizing structure-activity relationships and selectivity profiles of ligands [29] and to derive guidelines for lead-optimization studies, even in substitution of more computationally demanding procedures, such as free-energy perturbation approaches [30,31]. In these cases, the binding free energies of the complexes are calculated from several different snapshots extracted from the whole MD trajectory, in which ligand and protein can assume different conformations, and the final binding energy value is obtained by averaging the energies estimated for the different snapshots.…”