Development of a direct DUX4 inhibitor for Facioscapulohumeral Muscular Dystrophy (FSHD)
开发用于面肩肱型肌营养不良症 (FSHD) 的直接 DUX4 抑制剂
基本信息
- 批准号:10482575
- 负责人:
- 金额:$ 29.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmericanAnimalsAntibodiesAreaBindingBiological AssayCell DeathCell SurvivalCellsCessation of lifeClinicalClinical TrialsComputer softwareD4Z4DNADNA BindingDNA Binding DomainDevelopmentDiagnosisDiseaseDrug KineticsEctopic ExpressionExhibitsFDA approvedFaceFacioscapulohumeralFacioscapulohumeral Muscular DystrophyGenesGenetic TranscriptionGrantHomeoboxHumanImpairmentImplantIndividualLeadLinkMeasuresMesenchymal Stem CellsMessenger RNAMusMuscleMuscle CellsMuscle FibersMuscular AtrophyMuscular DystrophiesMyoblastsMyosin Heavy ChainsNormal CellOpen Reading FramesOsteoblastsOutcome MeasurePAX3 genePAX7 genePathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhasePloidiesPositioning AttributeProgressive DiseasePublishingQuality of lifeQuantitative Reverse Transcriptase PCRReporterShoulderSignal TransductionSkeletal MuscleSmall Business Innovation Research GrantSmall Interfering RNASpecificityStainsSurfaceTestingTherapeuticToxic effectUnited StatesUniversitiesUpper armWheelchairsXenograft ModelXenograft procedureappropriate dosebarium chloridebasecommercializationcytotoxiccytotoxicitydrug candidatedrug developmenteffective therapyfluorescence microscopehuman DNAin silicoin vivoinhibitorlocked nucleic acidmouse modelmuscle degenerationmyogenesisnovelp38 Mitogen Activated Protein Kinasepreventprotein protein interactionscreeningside effectsmall moleculesmall molecule inhibitorsuccesstargeted treatmenttherapeutic targettibialis anterior muscletranscription factortranslational impact
项目摘要
Abstract/Summary
Facioscapulohumeral dystrophy (FSHD) is the third most common form of muscular dystrophy affecting over
30,000 Americans. FSHD is a progressive disease where patients initially lose muscle cells in the face, shoulders
and upper arms before degeneration expands to include nearly all skeletal muscles and 20% become wheelchair
bound. 95% of FSHD patients display a contraction of the highly polymorphic D4Z4 repeat (FSHD1) containing
an open reading frame for the transcription factor (TF) Double Homeobox 4 (DUX4). DUX4 misexpression is
associated with myoblast toxicity and is thought to be the driver of FSHD. It is believed that DUX4 induces
myoblast death by upregulating target genes including MBD3L2, TRIM43, ZSCAN4, and LEUTX that are not
normally expressed in muscle. Although there are no FDA approved therapies for FSHD, losmapimod, a small
molecule p38 inhibitor, was shown to inhibit DUX4 transcription in FSHD patient cells and demonstrated clinical
benefit in several outcome measures. However, losmapimod is not specific to DUX4 and FSHD, therefore
developing multiple targeted therapies with different modes of inhibition would increase the success rate in
treating FSHD with minimum long term side effects. We hypothesize that targeting DUX4 will block multiple
pathways and reduce muscle cell death. Although TFs like DUX4 are attractive therapeutic targets, they are
challenging to target with small molecules because they lack clear binding pockets, have large surface areas
important for protein-protein interactions and contain large intrinsically disordered domains. At Altay
Therapeutics, we developed a platform that enables identification of small binding pockets within intrinsically
disordered domains in previously undruggable TFs, allowing a novel druggable approach for targeting DUX4
and development of potent and highly specific DUX4 inhibitors (DUX4i). We completed in-silico screening and
identified inhibitors that reduced DUX4 DNA binding by targeting the disordered linker domain. Importantly, these
DUX4i had minimal cytotoxicity, reduced DUX4 target genes and rescued DUX4 driven cell viability, important
to treat FSHD. We propose three aims to identify and characterize the most promising lead and continue our
efforts to develop a viable treatment for FSHD based on inhibiting DUX4. The successful completion of our
proposal is intended to nominate a lead DUX4 drug candidate with the following aims, 1) Determine DUX4 target
gene inhibition with our DUX4is and measure cytotoxicity in a broader panel of normal cells 2) Determine
specificity of our DUX4is against other homeobox-containing genes such as PAX3/PAX7 and measure potential
non-specific inhibition of normal myoblast differentiation 3) Measure in vivo efficacy of DUX4is in mice implanted
with human FSHD myoblasts in the tibialis anterior muscles (xenograft model of FSHD). We will then pursue an
SBIR phase 2 grant that will include medicinal chemistry efforts and additional animal studies and ultimately
commercialization of a first-in-class DUX4 inhibitor for FSHD. The development of the first direct DUX4 inhibitor
will position Altay Therapeutics to initiate clinical trials in FSHD to ultimately bring a much-needed therapy.
抽象/总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ali Rayet Ozes其他文献
Ali Rayet Ozes的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ali Rayet Ozes', 18)}}的其他基金
The development of a transcriptional inhibitor for lung fibrosis.
肺纤维化转录抑制剂的开发。
- 批准号:
10489942 - 财政年份:2022
- 资助金额:
$ 29.96万 - 项目类别:
Novel STAT3 inhibitor for overcoming chemoresistant ovarian cancer .
用于克服化疗耐药性卵巢癌的新型 STAT3 抑制剂。
- 批准号:
10547366 - 财政年份:2022
- 资助金额:
$ 29.96万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 29.96万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 29.96万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 29.96万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 29.96万 - 项目类别:
Studentship