Serine Hydrolase Superfamily
With over 250 members, the serine hydrolase superfamily is one of the largest known enzyme families in human biology. Serine hydrolases encompass many classes of enzymes, including lipases, esterases, proteases, and peptidases, and play key roles in a wide array of biological processes ranging from blood clotting to synaptic signaling to the life cycles of pathogens. Serine hydrolases share a common catalytic mechanism, but act on a diverse array of substrate classes, thereby participating in nearly all areas of biology and disease.
An Untapped Resource
Well-known blockbuster drugs have emerged from targeting biological processes modulated or regulated by human serine hydrolases, and there are approved small-molecule serine hydrolase inhibitors for the treatment of a wide variety of indications, including type 2 diabetes, Alzheimer’s disease, and infectious diseases. However, we believe this is only the beginning. Many serine hydrolases regulate signaling molecules such as neurotransmitters and hormones. By targeting serine hydrolases we can modulate endogenous signaling pathways through adjusting the levels of natural receptor ligands. For example, monoacylglycerol lipase (MGLL) is responsible for inactivation of the endocannabinoid 2-arachidonoylglycerol (2AG), an endogenous ligand for the cannabinoid receptors CB1 and CB2. Abide’s first clinical compound, ABX-1431, modulates the tissue concentrations of both 2-AG and arachidonic acid, signaling molecules involved in pain and inflammation. This modulation is achieved through inhibition of MGLL; thus, ABX-1431 is expected to combine analgesic and anti-inflammatory effects.
Despite both clinical and commercial validation, the serine hydrolase family has been under-explored for novel therapeutics, with only three members of the mammalian family developed as drug targets in the last 50 years. Most human serine hydrolases remain poorly characterized with respect to biological functions and substrates, in part due to a dearth of available pharmacological tools to probe their functions. Abide’s proprietary chemical library is capable of interrogating the functions of a majority of the serine hydrolome, and is being used to discover new roles for uncharacterized enzymes in physiology and disease.
Abide’s platform provides unique opportunities to discover novel targets that are directly relevant to human disease, and the efficient evolution of our tool compounds into drug candidates provides us with unprecedented advantages in realizing the therapeutic potential of novel serine hydrolase inhibitors.