Identification and development of cGAS inhibitors and their uses to treat Alzheimer's disease.

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key component of the evolutionary conserved immune response pathway, acting upstream stimulator of interferon genes (STING). It is implicated in various human diseases, including Alzheimer's Disease (AD) and other neurodegenerative disorders. Recent studies have shown that pharmacological inhibition of cGAS in tauopathy mice reduces cytokine expression and ameliorates memory and cognition function. This review summarizes the development and application of high-throughput screening (HTS) strategies for identifying cGAS inhibitor hits and transitioning from hits to leads. Such efforts have provided diverse array of potent cGAS inhibitors that may be beneficial in treating central nervous system (CNS) disorders, such as AD and other neurodegenerative diseases. We describe three HTS strategies: the classical HTS using a chemical library of drug like compounds by cell-free or cell-based assays and the fragment-based screening, where the activity of potential inhibitors was determined by measuring the levels of unreacted ATP or assessing the production of cGAMP or pyrophosphate (PPi). These methods were instrumental in discovering cGAS inhibitor hits and subsequent modifications produced potent leads. Finally, we discuss various post-translational modifications of cGAS and consider whether some of these modifications may serve as useful targets for inhibiting cGAS activity or for promoting protein degradation.