Preclinical Validation of Novel Gut-Restricted LRRK2 Inhibitors as Therapeutic Leads for IBD

新型肠道限制性 LRRK2 抑制剂作为 IBD 治疗先导药物的临床前验证

基本信息

项目摘要

SUMMARY Therapies to treat Crohn's disease (CD) and ulcerative colitis (UC), the types of inflammatory bowel disease (IBD) characterized by severe chronic inflammation of the gastrointestinal tract, have greatly improved over the past three decades; yet, a large proportion of IBD patients fail to achieve sustained remission. Genetic biomarkers may offer an avenue toward the dissecting heterogeneity of disease etiology, and improving personalized therapeutic approaches. Our group has recently identified a coding gain-of-function mutation in the LRRK2 (leucine-rich repeat kinase 2) gene that conferred a ~70% increased CD risk and affected CD age of onset, disease location, LRRK2 kinase activity, and autophagy flux. Importantly, LRRK2 has also attracted considerable attention for its causal link to Parkinson's disease (PD). Further analyses identified dozens of additional variants within LRRK2 that were associated with the risk of both CD and PD, suggesting shared pathogenesis between these diseases. Given extensive efforts to target LRRK2 kinase activity as a means to treat PD, we explored known LRRK2 inhibitors developed for PD as potential therapies for IBD. We showed that selective LRRK2 inhibitors have ameliorated experimental colitis and reduced inflammatory cytokine TNF-α levels, a hallmark of IBD-associated inflammation, in dendritic cells of IBD patients. However, studies of LRRK2 kinase inhibition in preclinical models suggest that brain penetration and toxicity in peripheral tissues may be a critical safety liability for these inhibitors in IBD patients. To advance this therapeutic hypothesis, we have developed structure-based approach to design novel gut-restricted LRRK2 inhibitors, synthesized prototype inhibitors, crystallized analogs in complex with kinases mutants that mimic LRRK2 binding site and tested their LRRK2 potency and efficacy, which are maintained. Thus, we are proposing, starting from known LRRK2 inhibitor structures to 1) Develop proof-of-concept gut-restricted LRRK2 inhibitors as potential IBD therapeutics using structure-based drug design and medicinal chemistry; 2) Evaluate novel compounds for LRRK2 inhibition, in vitro absorption, distribution, metabolism, excretion and pharmacokinetics, off-target selectivity, and effects on cellular substrate phosphorylation and cytokine activity using biochemical and cell-based assays, and 3) Pre- clinically validate new inhibitors for in vivo absorption, distribution, metabolism, excretion and pharmacokinetics, plasma exposures, and effects on inflammatory biomarkers and severity of experimental colitis. Our hypothesis is that gut-restricted LRRK2 inhibitors could be a safe and effective therapeutic target of IBD therapy in the presence or absence of IBD-associated LRRK2 mutations. These studies will provide a basis for future clinical trials aimed at testing LRRK2 as an effective drug target for IBD. We believe our strong preliminary data and relevant therapeutic hypothesis align well with the research goals and objectives of PAR-19-294 and will help improve the current standard of clinical care for patients with this disease of interest to the National Institute of Diabetes and Digestive and Kidney Diseases.
总结 治疗克罗恩病(CD)和溃疡性结肠炎(UC)的疗法,炎症性肠病的类型 (IBD)其特征在于严重的慢性胃肠道炎症,大大改善了 在过去的三十年中,大部分IBD患者未能实现持续缓解。遗传 生物标志物可以提供一种途径,以解剖疾病病因学的异质性,并改善 个性化的治疗方法。我们的研究小组最近发现了一个编码功能获得性突变, LRRK 2(富含亮氨酸的重复激酶2)基因,使CD风险增加约70%,并影响CD年龄 发病、疾病位置、LRRK 2激酶活性和自噬通量。重要的是,LRRK 2还吸引了 帕金森氏病(PD)是帕金森氏病的一种常见病。进一步分析发现, LRRK 2中的其他变异与CD和PD的风险相关,提示共享 这些疾病之间的关系。考虑到靶向LRRK 2激酶活性作为一种手段的广泛努力, 为了治疗PD,我们探索了为PD开发的已知LRRK 2抑制剂作为IBD的潜在疗法。我们发现 选择性LRRK 2抑制剂可改善实验性结肠炎并减少炎性细胞因子TNF-α 水平,IBD相关炎症的标志,在IBD患者的树突状细胞。然而,LRRK 2的研究 临床前模型中激酶抑制表明,脑渗透和外周组织中的毒性可能是 这些抑制剂在IBD患者中的关键安全性责任。为了推进这一治疗假设,我们有 开发基于结构的方法来设计新型肠道限制性LRRK 2抑制剂,合成原型 抑制剂,与模拟LRRK 2结合位点的激酶突变体复合的结晶类似物,并测试了它们的 LRRK 2的效力和功效得以维持。因此,我们建议从已知的LRRK 2开始, 1)开发概念验证的肠限制性LRRK 2抑制剂作为潜在的IBD治疗剂 使用基于结构的药物设计和药物化学; 2)评价用于LRRK 2抑制的新化合物, 体外吸收、分布、代谢、排泄和药代动力学、脱靶选择性以及对 使用生物化学和基于细胞的测定的细胞底物磷酸化和细胞因子活性,和3)预- 临床验证新抑制剂的体内吸收、分布、代谢、排泄和药代动力学, 血浆暴露,以及对炎症生物标志物和实验性结肠炎严重程度的影响。我们的假设 肠限制性LRRK 2抑制剂可能是IBD治疗的安全有效的治疗靶点, 存在或不存在IBD相关的LRRK 2突变。这些研究将为今后的临床应用提供依据。 试验旨在测试LRRK 2作为IBD的有效药物靶标。我们相信我们强大的初步数据, 相关的治疗假设与PAR-19-294的研究目标和目的一致, 提高目前的临床护理标准,为患者的利益,这种疾病的国家研究所 糖尿病、消化系统和肾脏疾病。

项目成果

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Robert J DeVita其他文献

Robert J DeVita的其他文献

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{{ truncateString('Robert J DeVita', 18)}}的其他基金

Allosteric regulation of lysine degradation as a novel pathophysiological mechanism in glutaric aciduria type 1
赖氨酸降解的变构调节作为 1 型戊二酸尿症的一种新的病理生理机制
  • 批准号:
    10720740
  • 财政年份:
    2023
  • 资助金额:
    $ 40万
  • 项目类别:
Preclinical Validation of Novel Gut-Restricted LRRK2 Inhibitors as Therapeutic Leads for IBD
新型肠道限制性 LRRK2 抑制剂作为 IBD 治疗先导药物的临床前验证
  • 批准号:
    10706472
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
A novel treatment option for disorders of propionate metabolism
丙酸代谢紊乱的新治疗选择
  • 批准号:
    10284208
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Substrate reduction as a novel therapeutic strategy for Glutaric Aciduria Type 1
减少底物作为 1 型戊二酸尿症的新型治疗策略
  • 批准号:
    10396619
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Substrate reduction as a novel therapeutic strategy for Glutaric Aciduria Type 1
减少底物作为 1 型戊二酸尿症的新型治疗策略
  • 批准号:
    10216580
  • 财政年份:
    2021
  • 资助金额:
    $ 40万
  • 项目类别:
Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration
人类 β 细胞再生的生物和药物化学方法
  • 批准号:
    10025889
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10434891
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Biological and Medicinal Chemistry Approaches to Human Beta Cell Regeneration
人类 β 细胞再生的生物和药物化学方法
  • 批准号:
    10363716
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10030712
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents
通过小分子试剂调节 Cullin-RING E3 泛素连接酶
  • 批准号:
    10668982
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:

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