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
• 负责人: Andrew Berglund
• 金额: $ 50.98万
• 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/10453985
• 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; 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; Testing; Therapeutic; Toxic effect; Transcript; Weight; base; benzimidazole; design; drug candidate; efficacy study; efficacy testing; 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 在超过40种神经肌肉和神经退行性重复扩张疾病的不断增长的家族中， 包括强直性肌营养不良（DM），涉及具有毒性的强RNA功能获得（GOF）机制 由扩增RNA诱导。在这种机制中，扩增的RNA螯合RNA结合蛋白（RBP） 导致多个下游RNA加工途径的破坏。扩大的减少 因此，RNA缓解疾病机制和下游发病机制是一种有吸引力的治疗方法 approach.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 介导的从扩增的CTG重复序列的选择性转录减少;（2）微管抑制剂介导的 毒性CUG RNA水平的选择性调节;和（3）二脒介导的毒性RNA的减少。而 这些结果显示出希望，其中许多化合物是有毒的，并显示出次优的性质， 开发一套新的改性多环化合物（MPC）。这些化合物基于三种 元件：杂环核;苯并咪唑侧基;和官能化端基。修改每个 这些元素提供了大量潜在化合物，以帮助理解作用机制 并开发新的候选药物，以解决糖尿病迫切的未满足的治疗需求。年的初步数据 这些MPC中的两种在纳摩尔范围内在DM 1和DM 2细胞系中都显示出对剪接的稳健拯救 几乎没有相关毒性或对细胞活力的影响，以及在2例独立DM中挽救错误剪接 小鼠模型。在本提案中，我们将使用平行的体外和体内设计-模型-测试循环， 系统地修改和评估化合物，重点放在替换，测试和完善的 三个MPC元件（核心、侧基和端基）。这些数据将有助于更好地了解他们的 作用机制，并随后测试其在DM患者来源的细胞中的治疗潜力 线和动物模型。该项目的成功完成将提供一种新的治疗方法， 小分子，更好地了解其作用机制和来自多种动物体内数据 支持其未来治疗潜力的模型。这些信息将共同解决大 未满足的糖尿病治疗方法需求，并为未来的临床研究提供支持数据。