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: 10612955
• 负责人: Andrew Berglund
• 金额: $ 48.84万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10612955
• 关键词: ABCB1 gene; Address; Affinity; Alleles; Animal Model; Binding; Biological Assay; Biological Availability; Biology; Brain; CUG repeat; Calorimetry; Cell Line; Cell Survival; Cell model; Clinical Research; Complex; DNA; DNA Maintenance; Dactinomycin; Data; Diamidine; Disease; Elements; Event; Exons; Family; Future; Genetic Transcription; Goals; Hand Strength; Hela Cells; Histopathology; In Vitro; Lead; Longitudinal Studies; Measures; Mediating; Microtubules; Modeling; Modification; Molecular; Muscle; Muscular Dystrophies; Myotonia; Myotonic Dystrophy; Nerve Degeneration; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Poison; Polycyclic Compounds; Property; Proteins; RNA; RNA Processing; RNA Splicing; RNA-Binding Proteins; Reverse Transcriptase Polymerase Chain Reaction; Series; Side; Solubility; System; Testing; Therapeutic; Toxic effect; Transcript; Weight; benzimidazole; candidate identification; candidate selection; design; drug candidate; efficacy study; gain of function; improved; in vivo; in vivo evaluation; inhibitor; lead candidate; melting; model design; molecular modeling; monolayer; mouse model; nanomolar; neuromuscular; novel therapeutics; preclinical study; small molecule; small molecule therapeutics; transcriptome sequencing; transcriptomics; uptake; water solubility

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/摘要 许多不断增长的40多个神经肌肉和神经退行性重复膨胀疾病的家族， 包括肌发育症（DM），涉及具有毒性的强RNA功能（GOF）机制 由扩展RNA诱导。在这种机制中，膨胀的RNA隔离RNA结合蛋白（RBP） 导致多个下游RNA处理途径的破坏。扩展的减少 因此，RNA减轻疾病机制和下游发病机理是一种有吸引力的治疗方法 方法。我们以前已经证明了有希望的小分子功效，包括：（1）放线菌素D 从扩展的CTG重复序列中介导的选择性减少转录； （2）介导的微管抑制剂 有毒CUG RNA水平的选择性调节； （3）二氨酸介导的毒性RNA降低。尽管 这些结果表明有希望，其中许多化合物具有毒性，并且显示出次优的特性。 开发一组新的修饰多环化合物（MPC）。这些化合物基于三个 元素：杂环核；一个苯咪唑侧组；和功能化最终组。修改每个 这些元素提供了大量的潜在化合物，以帮助理解作用机理 并开发新的候选药物，以满足DM中紧急未满足的治疗需求。初步数据 这些MPC中的两个显示了在纳摩尔范围内DM1和DM2细胞系中剪接的强大挽救 几乎没有相关的毒性或对细胞生存能力的影响以及在2个独立DM中挽救错误的误解 鼠标模型。在此提案中，我们将使用平行的体外和体内设计模式测试周期 通过专注于替换，测试和完善，系统地修改和评估化合物 三个MPC元素（​​核心，侧面和最终组）。这些数据将更好地了解他们的 作用机理，然后测试其在DM患者衍生细胞中的治疗潜力 线条和动物模型。该项目的成功完成将提供新的治疗性 小分子，更好地理解其作用机理和来自多个动物的体内数据 支持其未来治疗潜力的模型。总共这些信息将解决大型 对DM的治疗方法未满足，并为未来的临床研究提供支持数据。