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
- 来源:
- 关键词:Active SitesAfrican AmericanAnimal ModelApoenzymesAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmunityB-LymphocytesBindingBiochemicalBiological AssayBiological AvailabilityBloodBrainCause of DeathCell CycleCell DeathCell LineCell Membrane PermeabilityCellsCessation of lifeChronicClinicalClinical TrialsCollaborationsComplexCrystallizationCutaneousCyclic NucleotidesDNADataDetectionDinucleoside PhosphatesDrug TargetingEnzymesExposure toGene ExpressionGuanosine TriphosphateHeadHeartHispanicsHumanImmuneImmune responseInfiltrationInflammatoryInnate Immune ResponseInterferon Type IInterferon-alphaInterferon-betaInterferonsInvestigationKidneyKnock-outLeadLigandsLungLupusMedicalModelingMolecularMolecular ConformationMolecular WeightMonitorMusNucleic AcidsOralOral AdministrationOrganPainPathologyPathway interactionsPatientsPeriodicityPharmaceutical ChemistryPharmaceutical PreparationsPhasePhase I Clinical TrialsPhotosensitivityPhysiologicalProductionPropertyProteinsReportingResearchRheumatoid ArthritisRheumatologySafetySecond Messenger SystemsShipsSignal InductionSignal TransductionSkinSmall Business Innovation Research GrantStimulator of Interferon GenesStructureSunlightSymptomsSystemic Lupus ErythematosusT-Cell ActivationTestingTherapeuticTherapeutic InterventionTimeTissuesUV inducedUniversitiesWashingtonWomanWorkanimal efficacyautocrinebelimumabcommon symptomcurative treatmentscytokinedimerdrug candidatedrug developmentds-DNAefficacy evaluationefficacy studyimprovedin vivoinhibitor/antagonistinnovationlead optimizationmicrobialmonocytemonomermortalitymouse modelparacrinepathogenic microbeprematurereceptorresidenceresponsescaffoldsensorsmall molecule
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
我们正在开发环GAMP合成酶(cGAS)的小分子拮抗剂,以确定候选药物
狼疮的分子系统性红斑狼疮(SLE),或简称狼疮,是第二常见的
自身免疫性疾病仅次于类风湿性关节炎;仅在美国就有至少30万患者,
全球超过一百万。未得到满足的医疗需求是巨大的:狼疮患者的患病率增加了67%,
50%的病例中主要器官受损的死亡率;例如,心脏、肺、肾和大脑;狼疮是
2011年至2015年,美国年轻的非洲裔美国人和西班牙裔妇女的第五大死亡原因。
狼疮没有治愈性治疗方法,在过去的50年里只有一种药物(Benlysta)被批准。
狼疮病理是由I型干扰素(IFN)和免疫传感器环GAMP合酶驱动的
(cGAS)是I型IFN诱导的触发物。来自垂死细胞的DNA与无催化活性的cGAS结合,
一种激活的复合物,触发独特的环核苷酸第二信使环GAMP的产生
(cGAMP)。cGAMP与STING蛋白结合以诱导I型IFN的表达,具有自分泌和旁分泌作用。
导致T细胞和B细胞活化和自身抗体产生的作用,促使细胞恶性循环,
死亡和自身免疫
使用在单独SBIR下开发的创新HTS测定,我们发现了两种有前途的cGAS
拮抗剂化学型(40783和50101)通过不同的机制发挥作用,并取得了实质性进展
增加其生化和细胞效力,同时保持ADME特性,预测良好的口服给药效果。
生物利用度我们的结构数据表明,40783化学型具有变构结合特性,
稳定非活性cGAS构象,我们将在第二阶段利用这些性质来开发高度
具有长停留时间的选择性铅分子。50101化学型似乎特异性结合于
高致敏cGAS-Mn-DNA复合物,这可能导致改善的治疗窗口。在第二阶段,我们
建议:1)进一步优化两种化学型的效力、选择性和ADME性质,2)测试它们的
在UV诱导的光敏性的创新模型中的有效性,该模型复制了SLE病理学的关键方面,
这与我们的临床策略密切相关。动物有效性研究将与基思埃尔康合作进行,
西雅图的华盛顿大学的流变学负责人,他开发了小鼠光敏性模型,
开创了cGAS/STING通路参与狼疮的研究。
大多数研究性狼疮药物靶向I型干扰素的下游效应,这是一种类似于
把沉船上的洞堵上靶向cGAS的药物的开发,cGAS是癌症的上游分子触发剂。
核酸驱动的I型IFN产生可以彻底改变狼疮的治疗,沿着越来越多的cGAS-
导致自身免疫和炎症
项目成果
期刊论文数量(0)
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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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