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Development of caspase-6 inhibitors for treatment of NASH

开发治疗 NASH 的 caspase-6 抑制剂

基本信息

批准号：
10608905
负责人：
Michelle Arkin
金额：
$ 71.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2023-01-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608905
关键词：
5&apos -AMP-activated protein kinase Affect Affinity Animal Model Apoptosis Apoptotic Attenuated Binding Binding Proteins Biochemical Biological Assay Biological Availability Biological Markers Biopsy Specimen CASP3 gene CASP6 gene Caspase Caspase Inhibitor Cell Culture Techniques Cell model Cells Cessation of life Chemicals Chronic Clinical Clinical Research Clinical Trials Collaborations Cysteine Data Development Diet Drug Kinetics Enzyme Inhibitor Drugs Enzyme Precursors Enzymes Epidemic Fibrosis Funding Future Genomics Half-Life Hepatic Hepatocyte High Pressure Liquid Chromatography Human In Vitro Knock-out Laboratories Lead Ligands Liver Liver Fibrosis Measures Metformin Mitochondria Modeling Monitor Mus Mutation Obesity Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Play Process Property Proteins Proteomics Readiness Repression Roentgen Rays Role Safety Sampling Series Serum Small Interfering RNA Specificity Structure Testing Therapeutic Work analog biomarker identification clinical candidate clinical investigation cytochrome c design experience improved in vivo inhibitor insight knock-down knockout animal lead series liver injury mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel pharmacokinetics and pharmacodynamics pharmacologic preclinical development sensor targeted biomarker therapeutic target transcriptome sequencing

项目摘要

Abstract Hepatocellular death plays an essential role in the development of nonalcoholic steatohepatitis (NASH). The activity of the energy sensor AMP-activated kinase (AMPK) is repressed in NASH and nonalcoholic fatty liver disease (NAFLD). Recent studies from our laboratory demonstrate that AMPK normally phosphorylates the pro-apoptotic caspase-6 to inhibit its activation, keeping hepatocyte apoptosis in check. Steatosis-induced suppression of AMPK activity relieves this inhibition, rendering caspase-6 activated in both human and murine NASH. Activation of AMPK or inhibition of caspase-6, even after the onset of NASH, improves liver damage and fibrosis. Because caspase-6 is an attractive therapeutic target, we will develop high affinity and high specificity chemical inhibitors of caspase 6 for the treatment of NASH. We will pursue two series that are already well advanced, one that binds covalently to the enzyme with high affinity and specificity, and a second noncovalent series that stabilizes the inactive, zymogen state of caspase-6 and inhibits its activation. Selective inhibition of caspase-6 over other caspases has been difficult to achieve before now, but should be safe given the mild phenotype of caspase-6 knockout animals and patients with inactivating mutations. Using structure- based design, we will develop a clinical candidate based on affinity, specificity, ADME properties, bioavailability and in vivo activity in mouse models of NASH. We will also develop a biomarker for capsase-6 inhibition in vivo that will help guide future clinical trials. These efforts may lead to development of the first specific drug that directly attacks the pathogenic process underlying the development of human NASH.

摘要肝细胞死亡在非酒精性脂肪性肝炎（NASH）的发展中起着至关重要的作用。的能量传感器AMP激活激酶（AMPK）的活性在NASH和非酒精性脂肪肝中受到抑制非酒精性脂肪肝（NAFLD）。我们实验室最近的研究表明，AMPK通常磷酸化促凋亡半胱天冬酶-6抑制其活化，保持肝细胞凋亡在检查中。脂肪变性诱导 AMPK活性的抑制解除了这种抑制，使得在人和鼠中caspase-6被激活纳什AMPK的激活或caspase-6的抑制，即使在NASH发作后，也可改善肝损伤和纤维化。由于caspase-6是一个有吸引力的治疗靶点，我们将开发高亲和力和高亲和力的药物。用于治疗NASH的半胱天冬酶6的特异性化学抑制剂。我们将追求两个系列，已经很先进，一个是共价结合的酶具有高亲和力和特异性，和第二个稳定半胱天冬酶-6的无活性酶原状态并抑制其活化的非共价系列。选择性在此之前，相对于其他半胱天冬酶，半胱天冬酶-6的抑制是难以实现的，但是给予 caspase-6敲除动物和失活突变患者的轻度表型。使用结构- 基于设计，我们将根据亲和力、特异性、ADME特性，在NASH小鼠模型中的生物利用度和体内活性。我们还将开发一种capsase-6的生物标志物这将有助于指导未来的临床试验。这些努力可能会导致第一个直接攻击导致人类NASH发展的致病过程的特异性药物。