Discovery of cGAS Inhibitors for Interferon-Driven Autoimmune Diseases

发现用于治疗干扰素驱动的自身免疫性疾病的 cGAS 抑制剂

基本信息

  • 批准号:
    10258171
  • 负责人:
  • 金额:
    $ 98.88万
  • 依托单位:
  • 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:
    2019-06-12 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Summary We are developing small molecule antagonists for cyclic GAMP synthase (cGAS) to identify a candidate drug molecule for lupus. Systemic lupus erythematosus (SLE), or simply lupus, is the second most common autoimmune disease next to rheumatoid arthritis; there are at least 300,000 patients in the U.S. alone and well over a million globally. The unmet medical need is enormous: lupus patients suffer from a 67% increase in mortality rate with damage to major organs in 50% of cases; e.g., heart, lung, kidneys, and brain; lupus was the 5th leading cause of death among young African American and Hispanic women in the U.S. from 2011-2015. There are no curative treatments for lupus, and only one drug (Benlysta) has been approved in the last 50 years. Lupus pathology is driven by type I interferons (IFNs), and the immune sensor, cyclic GAMP synthase (cGAS), is the trigger for type I IFN induction. DNA from dying cells binds to catalytically inactive cGAS to form an activated complex, triggering production of a unique cyclic nucleotide second messenger, cyclic GAMP (cGAMP). cGAMP binds to the STING protein to induce expression of type I IFNs, with autocrine and paracrine effects that lead to activation of T- and B-cells and auto-antibody production, precipitating a vicious cycle of cell death and autoimmunity. Using an innovative HTS assay developed under a separate SBIR, we discovered two promising cGAS antagonist chemotypes (40783 and 50101) that function via distinct mechanisms and have made substantial progress on increasing their biochemical and cellular potency while maintaining ADME properties predictive of good oral bioavailability. Our structural data indicate that the 40783 chemotype has allosteric binding properties and may stabilize an inactive cGAS conformation, properties which we will leverage in Phase II to develop a highly selective lead molecule with a long residence time. The 50101 chemotype appears to bind specifically to a hypersensitized cGAS-Mn-DNA complex, which could lead to an improved therapeutic window. In Phase II we propose to: 1) further optimize the potency, selectivity and ADME properties of the two chemotypes and 2) test their efficacy in an innovative model for UV-induced photosensitivity that replicates key aspects of SLE pathology and aligns closely with our clinical strategy. The animal efficacy studies will be performed in collaboration with Keith Elkon, Head of Rheumatology at University of Washington, Seattle, who developed the mouse photosensitivity model and has pioneered research on the involvement of the cGAS/STING pathway in lupus. Most investigational lupus drugs target the downstream effects of type I IFNs, a strategy that is akin to plugging holes in a sinking ship. The development of drugs that target cGAS, the upstream molecular trigger for nucleic-acid driven type I IFN production could revolutionize the treatment of lupus along with a growing list of cGAS- driven autoimmune and inflammatory conditions.
总结

项目成果

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Robert G Lowery其他文献

Robert G Lowery的其他文献

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{{ truncateString('Robert G Lowery', 18)}}的其他基金

Targeting a Human Acyltransferase for Broad-Spectrum Antivirals
靶向人类酰基转移酶的广谱抗病毒药物
  • 批准号:
    10223496
  • 财政年份:
    2021
  • 资助金额:
    $ 98.88万
  • 项目类别:
Discovery of cGAS Inhibitors for Interferon-Driven Autoimmune Diseases
发现用于治疗干扰素驱动的自身免疫性疾病的 cGAS 抑制剂
  • 批准号:
    10349593
  • 财政年份:
    2019
  • 资助金额:
    $ 98.88万
  • 项目类别:
HTS Assays for Targeting the cGAS-STING Pathway in Autoimmune Diseases and Cancer
针对自身免疫性疾病和癌症中的 cGAS-STING 通路的 HTS 检测
  • 批准号:
    9347049
  • 财政年份:
    2017
  • 资助金额:
    $ 98.88万
  • 项目类别:
Riboswitch Based Methyltransferase HTS Assay for Epigenetic Drug Discovery
基于核糖开关的甲基转移酶 HTS 测定用于表观遗传药物发现
  • 批准号:
    9266793
  • 财政年份:
    2014
  • 资助金额:
    $ 98.88万
  • 项目类别:
Riboswitch Based Methyltransferase HTS Assay for Epigenetic Drug Discovery
基于核糖开关的甲基转移酶 HTS 测定用于表观遗传药物发现
  • 批准号:
    8646158
  • 财政年份:
    2014
  • 资助金额:
    $ 98.88万
  • 项目类别:
Riboswitch Based Methyltransferase HTS Assay for Epigenetic Drug Discovery
基于核糖开关的甲基转移酶 HTS 测定用于表观遗传药物发现
  • 批准号:
    9140743
  • 财政年份:
    2014
  • 资助金额:
    $ 98.88万
  • 项目类别:
High Throughput Assay for Detecting Protein Modifications in Cell Lysates
用于检测细胞裂解物中蛋白质修饰的高通量测定
  • 批准号:
    8124311
  • 财政年份:
    2011
  • 资助金额:
    $ 98.88万
  • 项目类别:
Screening Device for Differentiated Primary Cell Models of Airway Epithelia
气道上皮分化原代细胞模型筛选装置
  • 批准号:
    8315901
  • 财政年份:
    2010
  • 资助金额:
    $ 98.88万
  • 项目类别:
Screening Device for Differentiated Primary Cell Models of Airway Epithelia
气道上皮分化原代细胞模型筛选装置
  • 批准号:
    8515510
  • 财政年份:
    2010
  • 资助金额:
    $ 98.88万
  • 项目类别:
Intramolecular Immunoassay for Probing Paracrine Signaling
用于探测旁分泌信号传导的分子内免疫分析
  • 批准号:
    8001695
  • 财政年份:
    2010
  • 资助金额:
    $ 98.88万
  • 项目类别:

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