Optimizing virtual hits of human CGAS inhibitors to treat neurodegeneration

摘要

Abstract Aeton Therapeutics is developing inhibitors of cGAS (cyclic GMP-AMP synthase)—a pattern recognition receptor that activates STING and results in the production of interferon (IFN)-β—as novel therapies for the treatment of Alzheimer’s disease (AD). AD is the most common form of late-onset dementia and affects nearly 50 million people worldwide and an estimated 5.7 million Americans. In 2020, total payments for healthcare, long‐term care, and hospice services for people aged 65 and older with dementia were estimated to be $305 billion. The cognitive decline associated with AD correlates with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Aeton Therapeutics seeks to produce a novel therapeutic for AD by developing cGAS inhibitors (cGASi’s). cGAS is a cytosolic DNA sensing protein that has been linked to a number of neurodegenerative and inflammatory diseases. Upon sensing DNA in the cytosol (due to the presence of pathogens, genomic/mitochondrial damage, or other pathological mechanisms), cGAS catalyzes ATP/GTP coupling to produce 2’3’-cGAMP, a potent ligand of STING, resulting in the production of IFN-β. Previous studies suggest that cGAS is aberrantly activated in a tauopathy mouse model, resulting in an IFN response and neurotoxic chronic neuroinflammation. In contrast, genetic ablation of cGAS in PS19 mice, which overexpress P301S mutant tau and develop tau pathology and cognitive deficits, protects against those cognitive deficits and the loss of hippocampal synapses. These findings strongly support the development of cGASi’s to protect against the negative effects of cGAS-STING hyperactivation, but existing compounds exhibit only modest potency in inhibiting the cGAS-STING pathway in human THP1 myeloid cells. To develop novel cGASi’s to treat tau-mediated neurodegeneration in AD, in this Phase I project, Aeton Therapeutics proposes the following aims: Aim 1. Develop potent h-cGASi’s via medicinal chemistry of virtual hits 1 and 2. We have identified promising hits via a virtual screen. We will perform optimization and in vitro assessment of h- analogs to identify lead candidates. Aim 2. Determine PK, target engagement, and efficacy of h-cGASi’s in human iPSC-derived microglia and organoid model. The two best leads showing high brain exposure will be assessed in PK studies in wild-type mice and evaluated in human iPSC-derived microglia and organoids. Lead h-cGASi’s must reduce key biomarkers, such as Cxcl4, Ifnb, and TBK1/pTBK1. We expect to identify at least one lead h-cGASi that reduces key biomarkers in cells and organoids, is brain permeable, shows no toxicity in mice, and does not have off-target effects. This will lead to development of novel cGASi’s that are likely to reprogram toxic microglial responses and protect against tau-related cognitive decline.