Jaiswal_2021_ChemMedChem__

Recently fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors have come in a limelight due to their anti-proliferative potential. Both FAAH and MAGL are the endocannabinoid degrading enzymes that hydrolyze several endogenous ligands, mainly anandamide (AEA) and 2-arachidonic glycerol (2-AG), which regulated the various pathophysiological condition of the body like emotion, cognition, energy balance, pain sensation, neuro-inflammation, and cancer cell proliferation. FAAH and MAGL inhibitors block the metabolism of AEA and 2-AG, and increases endogenous levels of fatty acid amides, and exert various therapeutic effects including chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders, etc. FAAH and MAGL are primarily neurotherapeutic targets but their contribution to various types of carcinomas are significant. Inhibitors of these enzymes either alone or multi-target or with supra-additive effect show the potential effect in ovarian, breast, prostate, and colorectal cancers. This review besides highlighting the role of FAAH and MAGL enzymes in cancer progression provides an update on the anti-proliferative capabilities of known and newly discovered FAAH and MAGL inhibitors and provides further directions to develop FAAH and MAGL inhibitors as new candidates for cancer therapy.