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

批准号：
10450467
负责人：
Robert J DeVita
金额：
$ 40万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2022-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450467
关键词：
Affect Age of Onset Alleles Anti-Inflammatory Agents Attention Autophagocytosis Binding Sites Biochemical Biological Assay Biological Markers Blocking Antibodies Blood Circulation Brain Cells Chemicals Chronic Clinical Trials Code Colitis Colonic inflammation Complex Crohn&apos s disease Crystallization Data Dendritic Cells Development Disease Disease remission Dose Drug Design Drug Kinetics Drug Targeting Enzymes Epithelial Etiology Excretory function Future Gastrointestinal tract structure General Population Genetic Markers Goals In Vitro Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Intellectual Property LRRK2 gene Lead Link Location Lung Medical Metabolism Monoclonal Antibodies Mus Mutate Mutation National Institute of Diabetes and Digestive and Kidney Diseases Operative Surgical Procedures Oral Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patient Care Patients Penetration Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Phosphotransferases Plasma Population Pre-Clinical Model Production Property Research Risk Roentgen Rays Safety Severities Structure TNF gene Testing Therapeutic Therapeutic Uses Time Tissues Toxic effect Ulcerative Colitis Validation Variant X-Ray Crystallography absorption analog base chemical group clinical care cytokine design disease heterogeneity disorder risk drug development drug discovery effective therapy gain of function mutation genome wide association study improved in vivo inhibitor interest interleukin-23 loss of function mutant nephrotoxicity novel personalized therapeutic pre-clinical prototype response safety testing scaffold side effect therapeutic target therapeutically effective

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.

概括治疗克罗恩病 (CD) 和溃疡性结肠炎 (UC)（炎症性肠病的类型）的疗法以胃肠道严重慢性炎症为特征的炎症性肠病 (IBD) 较过去三十年；然而，很大一部分 IBD 患者未能实现持续缓解。生物标志物可能为剖析疾病病因学的异质性提供一条途径，并改善我们的小组最近发现了编码功能获得性突变。 LRRK2（富含亮氨酸重复激酶 2）基因使 CD 风险增加约 70%，并影响 CD 年龄发病、疾病部位、LRRK2 激酶活性和自噬流也很重要。其与帕金森病 (PD) 的因果关系受到广泛关注，进一步分析发现了数十种原因。 LRRK2 内的其他变异与 CD 和 PD 的风险相关，表明共享鉴于针对 LRRK2 激酶活性的广泛努力，作为一种手段来研究这些疾病之间的发病机制。为了治疗 PD，我们探索了为 PD 开发的已知 LRRK2 抑制剂作为 IBD 的潜在疗法。选择性 LRRK2 抑制剂可改善实验性结肠炎并减少炎症细胞因子 TNF-α 然而，LRRK2 的研究表明，IBD 患者的树突状细胞中存在 LRRK2 水平，这是 IBD 相关炎症的一个标志。临床前模型中的激酶抑制表明，外周组织的脑渗透和毒性可能是为了推进这一治疗假设，我们提出了这些抑制剂在 IBD 患者中的关键安全性。开发了基于结构的方法来设计新型肠道限制性 LRRK2 抑制剂，并合成了原型抑制剂，与激酶突变体复合的结晶类似物，模拟 LRRK2 结合位点并测试了它们的因此，我们建议从已知的 LRRK2 开始。抑制剂结构 1) 开发肠道限制性 LRRK2 抑制剂作为潜在的 IBD 疗法的概念验证使用基于结构的药物设计和药物化学；2) 评估新化合物对 LRRK2 的抑制作用，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化和基于细胞的测定法检测细胞底物磷酸化和细胞因子活性，以及 3) 预经过临床验证的体内吸收、分布、代谢、排泄和药代动力学的新型抑制剂，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。肠道限制性 LRRK2 抑制剂可能是 IBD 治疗的安全有效的治疗靶点这些研究将为未来的临床提供基础。旨在测试 LRRK2 作为 IBD 有效药物靶点的试验我们相信我们强有力的初步数据和。相关假设与 PAR-19-294 的研究治疗目标和目标非常吻合，并将有助于提高国家研究所感兴趣的这种疾病患者的当前临床护理标准糖尿病、消化系统疾病和肾脏疾病。