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cGAS inhibitors for Alzheimer's disease treatment

用于治疗阿尔茨海默病的 cGAS 抑制剂

基本信息

批准号：
10316803
负责人：
Li Gan
金额：
$ 84.75万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316803
关键词：
ABCB1 gene Ablation Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antiviral Agents Antiviral Response Behavior Biochemical Biological Biological Assay Brain Cells Cerebrum Chronic Clinical Trials Cognitive deficits Coupling Cyclic GMP DNA Dementia Development Disease Docking Drug Kinetics Drug Targeting Elderly Evaluation Exhibits Gene Proteins Generations Genes Genetic Genetic study Goals Guanosine Triphosphate Hippocampus (Brain)Histology Human Human Genetics Immune Immune response Impaired cognition In Vitro Inflammatory Innate Immune Response Interferon Activation Interferon Type I Interferon-beta Interferons Late Onset Alzheimer Disease Lead Learning Ligands Link Liver Liver Microsomes Measures Mediating Memory Loss Memory impairment Metabolic Metabolism Microglia Modeling Mus Myelogenous Myeloid Cells Neurofibrillary Tangles Neurons Organoids Pathologic Pathology Pathway interactions Permeability Pharmaceutical Preparations Phase Plasma Play Preclinical Testing Production Property Proteins Risk Role Screening Result Second Messenger Systems Senile Plaques Signal Transduction Source Stimulator of Interferon Genes Structure Structure-Activity Relationship Synapses Tauopathies Tissues Toxic effect Wild Type Mouse analog base behavior test beta amyloid pathology cytokine design drug candidate drug discovery ds-DNA efficacy study experimental study human stem cells hyperphosphorylated tau improved in silico in vivo in vivo evaluation inhibitor/antagonist luminescence mouse model nanomolar nervous system disorder neuroinflammation neurotoxic next generation novel novel lead compound overexpression preclinical study preference protective effect response risk variant sensor small molecule small molecule inhibitor success tau Proteins tau mutation therapeutic target tool transcriptomics

项目摘要

ABSTRACT Alzheimer's disease (AD) is the most common form of dementia in elderly. Amyloid-β (Aβ) and tau pathologies and neuroinflammation are three major hallmarks of Alzheimer's disease. Vast majority of the drug discovery efforts in the past decades have focused on targeting the Aβ pathology, but none are successful in Clinical Trials. While tau pathology, not the Aβ pathology, has emerged to play critical role in memory decline in AD, drugs targeting the direct effects of tau on neurons also have not met success either. Compelling human genetic studies link the innate immune responses to elevated risk of developing late-onset AD, supporting targeting microglia, resident immune cells in the brain, as the next-generation treatment for AD. We showed that a critical role of cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling in microglial toxicity and tau-mediated cognitive decline. Activation of cGAS, a major cytosolic dsDNA sensor, catalyzes production of cGAMP, an extremely potent STING agonist as the second messenger that activates cGAS-STING pathway, leading to a production of the antiviral responses through activation of interferon regulatory factors (IRFs) and expression of cytokine and type I interferon genes. We found that a partial or complete genetic cGAS ablation protected against the tau-mediated spatial learning and memory deficits in PS19 Tau mice. Moreover, treatment with a small molecule inhibitor of cGAS reduces interferon responses, diminished microgliosis, and protected against cognitive deficits in an AD mouse model with tauopathy. We hypothesize that inhibitors the cGAS activity will dampen neuroinflammation and maladaptive immune responses, protect against AD-related deficit. We propose to develop small molecule human cGAS (h-cGAS) inhibitors as novel microglial modulators to treat AD. In Aim 1, we will develop lead h-cGAS inhibitors starting with two known hits and determine whether these inhibitors effectively modulate the cGAS-STING pathway in cell-free and cell-based assays. We expect to identify new hits via hits expansion and synthesize >200 analogs. Aim 2 focuses on optimization of analogs a potent cGAS inhibitor, TDI-6570, which is a lead low nanomolar potent mouse cGAS (m-cGAS) inhibitor and possesses 10x less h-cGAS activity. We will design up to 50 new analogs. Results of SAR, docking experiments, and in- silico calculation will be used to maximize the lead quality. Completion of Aim 1 and Aim 2 will lead to 5 lead compounds for in vivo and efficacy studies. In Aim 3, we will establish PK and efficacy of h-cGAS inhibitors in mouse model of tauopathy, and efficacy in human stem cell-derived microglia and cerebral organoids with tauopathy. At the end of the proposed 5 years study, we anticipate identifying 1-2 lead h-cGAS inhibitors as tool compounds and a proof of principle to further advance as drug candidates to treat Alzheimer's disease and related neurological disorders.

摘要