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Development of small molecule cGAS inhibitors for repression of dsDNA-triggered interferon expression

开发用于抑制 dsDNA 触发的干扰素表达的小分子 cGAS 抑制剂

基本信息

批准号：
10404659
负责人：
THOMAS TUSCHL
金额：
$ 49.79万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404659
关键词：
Animals Autoimmune Autoimmune Diseases Autoimmune Responses Binding Biochemical Biological Assay Biological Process Biology Cancer cell line Cancerous Cell Aging Cell Lineage Cell physiology Cells Cellular Assay Cellular Stress Characteristics Chemicals Chromosomal Instability Collaborations Communities Complex Crystallization Cyclic GMP Cytosol DNA Development Dinucleoside Phosphates Disease Disease model Double-Stranded RNA Drug Industry Drug Screening Enzymes Event Extravasation Genes Genetic Goals Human Immune Industry Standard Inflammatory Innate Immune Response Institutes Institution Intellectual Property Interferon Type I Interferons Invaded Joints Knock-out Laboratories Lead Libraries Mass Spectrum Analysis Mediating Membrane Methods Mitochondria Modeling Mus Myelogenous Myeloid Cells Names Natural Immunity Neoplasm Metastasis Neurodegenerative Disorders Nuclear Nucleic Acids Obesity Parkinson Disease Pathway interactions Patients Periodicity Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Production Repression Research Personnel Resources Role Rupture STING1 gene Second Messenger Systems Specificity Stimulator of Interferon Genes Structure Systemic Lupus Erythematosus TREX1 gene Testing Therapeutic Toll-like receptors Validation antagonist autoinflammatory base biomaterial compatibility cell type cheminformatics cost cost effective cytokine design ds-DNA efficacy testing exodeoxyribonuclease high throughput screening human disease improved inhibitor insight interest loss of function mutation luminescence lupus-like macrophage novel novel therapeutics pathogen phosphodiester prevent programs pseudotoxoplasmosis syndrome response scaffold screening sensor small molecule small molecule inhibitor structural biology tool tumorigenesis

项目摘要

Cyclic GMP-AMP synthase (cGAS) is the primary sensor for cytosolic dsDNA, producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid-lineage cell types and responsible for providing innate immunity. Aberrant cytosolic dsDNA contributes to inflammatory diseases, suggesting that inhibition of cGAS may be therapeutically beneficial. We recently developed a mass- spectrometry-based high throughput screen (HTS) using mouse cGAS and identified small-molecule inhibitors that yielded the first active and specific inhibitors of cGAS in mouse cellular assays, albeit with no inhibitory activity in human cells. We now developed a faster and more cost effective HTS for identification of human cGAS inhibitors using chemiluminescence and screened 300,000 compounds. Subsequent medicinal chemistry optimization identified potent and specific inhibitors for human cGAS active in major interferon- producing cell types including primary macrophages and PBMCs. We have also solved co-crystal structures of inhibitors with human cGAS, suggesting structure- and computational-guided optimization path for the lead inhibitors. We propose to identify new hit compounds to access additional drug scaffolds through extended drug library screening to continue supporting our medicinal chemistry program. Using the most potent and specific inhibitors, we wish to characterize their inhibitory effect and pathway specificity in a more diverse range of cells. Our long-term goal is to develop therapeutics for cGAS-dysregulation associated diseases. This proposal is organized in 3 aims: (1) Identify new chemical scaffolds by HTS and apply cheminformatic analysis and medicinal chemistry hit optimization. We will use our newly established and validated HTS method for identification of human cGAS inhibitors to screen a newly available library of 100,000 compounds. New hit compounds will be prioritized for further derivatization to optimize potency and drug-like characteristics. (2) Structure/computation-guided design for optimization of new scaffolds and lead human cGAS inhibitors. We will use the insights gained from inhibitor-cGAS co-crystal structures to design, synthesize, and test derivatives to probe for the most potent, and promising drug-like cGAS inhibitor(s). (3) Develop new cellular validation assays for the identification of potent and highly selective cGAS inhibitors. We propose to evaluate and validate new and recently identified inhibitors by assessing their efficacy, selectivity, and biocompatibility using established and new cellular assays including non-myeloid cancer cell lines with chromosomal instability, primary myeloid cells, and patient-derived myeloid cells. Although initially discovered as central dsDNA sensor for antiviral activity, cGAS is also emerging as a player in obesity, neurodegenerative diseases, tumorigenesis, and cancer metastasis. Well-characterized, validated, potent, and specific cGAS inhibitors are needed in the community studying cGAS-STING biology as well as for treating cGAS-related inflammatory diseases!

环GMP-AMP合成酶（cGAS）是胞质dsDNA的主要传感器，产生环二核苷酸