Optimizing brain penetrance of caspase-6 inhibitors to treat neurodegenerative diseases

优化 caspase-6 抑制剂的脑外显率来治疗神经退行性疾病

基本信息

批准号：
10603619
负责人：
Michelle Arkin
金额：
$ 18.04万
依托单位：
ELGIA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603619
关键词：
Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Apoptosis Award Binding Biochemical Biological Assay Biological Availability Biological Markers Brain CASP6 gene Caspase Caspase Inhibitor Cell Death Cell model Cells Chemicals Chronic Complex Cysteine Data Development Disease Disease Progression Disease model Dose Drug Kinetics Drug or chemical Tissue Distribution Environmental Risk Factor Enzymes Family Fibrosis Foundations Funding Future Genetic Goals Half-Life Hand Hand functions Harvest Hour Human Inflammation Kinetics Knock-out Lead Measurement Measures Metabolism Modeling Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oral Patients Penetrance Penetration Peptide Hydrolases Perfusion Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Study Phase Phenotype Plasma Property Proteins Proteolysis Proteome Resistance Running Senile Plaques Series Serum Small Business Technology Transfer Research Structure Therapeutic Toxic effect Work analog brain tissue clinical candidate data modeling design experimental study familial Alzheimer disease human model improved in vivo inhibitor lead optimization member mouse model nanomolar neuroinflammation nonalcoholic steatohepatitis novel pharmacokinetics and pharmacodynamics pharmacologic phase 2 study presenilin programs protein aggregation proteostasis scaffold tau Proteins tau aggregation

项目摘要

PROJECT SUMMARY/ABSTRACT The cysteine protease caspase-6 (Casp6) has been associated with neurodegenerative diseases for over fifteen years. In Alzheimer’s disease (AD), Casp6 is colocalized with amyloid plaques and tau tangles in human brain, and both human and animal model data indicate that activated Casp6 contributes to neuronal inflammation, neurodegeneration, and cleavage of proteins to toxic forms. Humans and mice lacking Casp6 are healthy and resistant to inflammation; furthermore, Casp6 knockout in 5xFAD mice bearing familial AD mutations in presenilin1 and amyloid beta precursor protein (APP) show reduced levels in neuronal degeneration and inflammation. Thus, selective inhibition of Casp6 could be safe and effective in treatment of AD. To this end, we propose to design, synthesize and profile potent and highly selective inhibitors of the activated form of Casp6 (aCasp6) based on our initial SAR established for SU110 and SU134. These novel compounds gain selectivity by binding covalently to a unique cysteine residue not found in other members of the caspase family. While both SU110 and SU134 have promising drug-like properties, including low nanomolar inhibition of aCasp6 in biochemical and cell-based assays, low toxicity, few off- targets in proteome-wide studies, serum exposures 100-fold higher than cellular IC50, 50-77% oral bioavailability, and up to 23% brain/plasma exposure, we will further explore the SAR to identify compounds with improved PK and brain penetration properties (Aim 1). We will conduct standard mouse PK experiments to determine oral bioavailability and to define structure–brain exposure relationships. For Aim 2, we have developed a click-based probe of aCasp6 binding that demonstrates sufficient potency and selectivity to use as an ex vivo activity-based probe of aCasp6. We will use this probe, in conjunction with aCasp6 protein half-life determination and measurement of the aCasp6 substrate tau, to determine the lifetime of target inhibition by optimized aCasp6 inhibitors in cells; these data will be used in Phase II of the project to assess target engagement in animals. From these SAR, PK and tissue distribution studies, we will identify the most appropriate compounds to conduct PD assays and disease models to be run during Phase II of the project. In the subsequent Phase II application, we will develop biomarker assays and evaluate changes in these biomarkers after treatment with optimized lead compound in the 5xFAD model and additional animal models of AD. The conclusion of Phase II studies will be refinement of the Target Candidate Profile and will anticipate the selection of a development candidate for IND-enabling studies.

项目概要/摘要半胱氨酸蛋白酶 caspase-6 (Casp6) 与神经退行性疾病有关在阿尔茨海默氏病 (AD) 中，Casp6 与淀粉样斑块共定位并已存在超过 15 年。人脑中的 tau 蛋白缠结，人类和动物模型数据均表明激活的 Casp6 导致神经元炎症、神经变性和蛋白质裂解成有毒形式。缺乏 Casp6 的人类和小鼠是健康的并且具有抵抗炎症的能力； 5xFAD 小鼠携带早老素敲除和淀粉样β前体家族性 AD 突变蛋白质（APP）显示神经变性和炎症水平降低，因此具有选择性。抑制Casp6可以安全有效地治疗AD。为此，我们建议：设计、合成和分析 Casp6 激活形式的有效且高度选择性的抑制剂 (aCasp6) 基于我们为 SU110 和 SU134 建立的初始 SAR。通过与其他成员中未发现的独特半胱氨酸残基共价结合来获得选择性 SU110 和 SU134 都具有良好的药物特性，包括在生化和细胞检测中对 aCasp6 具有低纳摩尔抑制作用，毒性低，副作用少全蛋白质组研究中的目标，血清暴露比细胞 IC50 高 100 倍，50-77% 口服生物利用度，以及高达 23% 的脑/血浆暴露，我们将进一步探索 SAR 以确定具有改善的 PK 和脑渗透特性的化合物（目标 1）。小鼠 PK 实验以确定口服生物利用度并定义结构-大脑暴露对于目标 2，我们开发了一种基于点击的 aCasp6 结合探针。表现出足够的效力和选择性，可用作基于离体活性的探针我们将使用该探针，结合 aCasp6 蛋白半衰期测定和测量 aCasp6 底物 tau，以确定目标抑制的寿命细胞中优化的aCasp6抑制剂；这些数据将用于该项目的第二阶段进行评估从这些 SAR、PK 和组织分布研究中，我们将确定动物的目标参与度。最适合进行 PD 测定和运行疾病模型的化合物该项目的第二阶段在随后的第二阶段应用中，我们将开发生物标志物检测。并评估用优化的先导化合物治疗后这些生物标志物的变化 5xFAD 模型和其他 AD 动物模型将完成 II 期研究。完善目标候选人概况，并预测开发项目的选择 IND 启用研究的候选人。