Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy
预防强直性肌营养不良的新型小分子疗法的设计、合成和功效
基本信息
- 批准号:10612955
- 负责人:
- 金额:$ 48.84万
- 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:2022-05-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneAddressAffinityAllelesAnimal ModelBindingBiological AssayBiological AvailabilityBiologyBrainCUG repeatCalorimetryCell LineCell SurvivalCell modelClinical ResearchComplexDNADNA MaintenanceDactinomycinDataDiamidineDiseaseElementsEventExonsFamilyFutureGenetic TranscriptionGoalsHand StrengthHela CellsHistopathologyIn VitroLeadLongitudinal StudiesMeasuresMediatingMicrotubulesModelingModificationMolecularMuscleMuscular DystrophiesMyotoniaMyotonic DystrophyNerve DegenerationOrganPathogenesisPathologyPathway interactionsPatientsPoisonPolycyclic CompoundsPropertyProteinsRNARNA ProcessingRNA SplicingRNA-Binding ProteinsReverse Transcriptase Polymerase Chain ReactionSeriesSideSolubilitySystemTestingTherapeuticToxic effectTranscriptWeightbenzimidazolecandidate identificationcandidate selectiondesigndrug candidateefficacy studygain of functionimprovedin vivoin vivo evaluationinhibitorlead candidatemeltingmodel designmolecular modelingmonolayermouse modelnanomolarneuromuscularnovel therapeuticspreclinical studysmall moleculesmall molecule therapeuticstranscriptome sequencingtranscriptomicsuptakewater solubility
项目摘要
Summary/Abstract
Many of the growing family of over 40 neuromuscular and neurodegenerative repeat expansion diseases,
including myotonic dystrophy (DM), involve a strong RNA gain-of- function (GOF) mechanism with toxicity
induced by expansion RNAs. In this mechanism, the expanded RNAs sequester RNA binding proteins (RBPs)
leading to the disruption of multiple downstream RNA processing pathways. The reduction of the expanded
RNAs to alleviate disease mechanism and downstream pathogenesis is therefore an attractive therapeutic
approach. We have previously demonstrated promising small molecule efficacy including: (1) actinomycin D
mediated selective reduction of transcription from expanded CTG repeats; (2) microtubule inhibitors mediated
selective modulation of toxic CUG RNA levels; and (3) diamidines mediated reduction of toxic RNAs. While
these results show promise, many of these compounds are toxic and display sub-optimal properties leading us
to develop a new set of modified polycyclic compounds (MPCs). These compounds are based on three
elements: a heterocyclic core; a benzimidazole side group; and functionalized end groups. Modifying each of
these elements provides a large panel of potential compounds to aid in understanding mechanism of action
and develop new drug candidates to address the urgent unmet therapeutic need in DM. Preliminary data for
two of these MPCs shows robust rescue of splicing in both DM1 and DM2 cell lines in the nanomolar range
with little associated toxicity or effects on cell viability as well as rescue of mis-splicing in 2 independent DM
mouse models. In this proposal, we will use parallel in vitro and in vivo design-model-test cycles to
systematically modify and evaluate compounds by focusing on replacement, testing and refinement of the
three MPC elements (core, side and end groups). These data will provide a better understanding of their
mechanism of action and be followed by testing of their therapeutic potential in DM patient-derived cell
lines and animal models. The successful completion of this project will provide a new class of therapeutic
small molecules, a better understanding of their mechanism of action and in vivo data from multiple animal
models supporting their future therapeutic potential. Taken together this information will address the large
unmet need for therapeutic approaches for DM and provide supporting data towards future clinical studies.
摘要/文摘
项目成果
期刊论文数量(0)
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Andrew Berglund其他文献
Andrew Berglund的其他文献
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{{ truncateString('Andrew Berglund', 18)}}的其他基金
Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy
预防强直性肌营养不良的新型小分子疗法的设计、合成和功效
- 批准号:
10841946 - 财政年份:2023
- 资助金额:
$ 48.84万 - 项目类别:
Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy
预防强直性肌营养不良的新型小分子疗法的设计、合成和功效
- 批准号:
10841887 - 财政年份:2023
- 资助金额:
$ 48.84万 - 项目类别:
Design, synthesis and efficacy of new small molecule therapeutics to impede myotonic dystrophy
预防强直性肌营养不良的新型小分子疗法的设计、合成和功效
- 批准号:
10453985 - 财政年份:2022
- 资助金额:
$ 48.84万 - 项目类别:
Determining the factors that control dose-dependent splicing regulation by a master regulator
确定主调节器控制剂量依赖性剪接调节的因素
- 批准号:
9902459 - 财政年份:2017
- 资助金额:
$ 48.84万 - 项目类别:
Determining the factors that control dose-dependent splicing regulation by a master regulator
确定主调节器控制剂量依赖性剪接调节的因素
- 批准号:
9383785 - 财政年份:2017
- 资助金额:
$ 48.84万 - 项目类别:
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