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Development of lysosome targeted therapeutics

溶酶体靶向治疗药物的开发

基本信息

批准号：
10482643
负责人：
Jennifer S Carew
金额：
$ 25.83万
依托单位：
MAJESTIC THERAPEUTICS, LLC
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：
2022-07-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482643
关键词：
Acute Myelocytic Leukemia Address Affect Antimalarials Autophagocytosis Azacitidine Cell Survival Cellular Stress Chemistry Clinical Development Disease Disease Progression Dose Drug Design Drug resistance Elderly Exhibits FDA approved Funding Generations Goals Homeostasis Hydroxychloroquine Hypoxia In Vitro Inferior Lead Lysosomes Malignant - descriptor Malignant Neoplasms Medical Metabolic Modeling Modification Mutation Myelogenous Oral Organelles Outcome Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Positioning Attribute Process Prognosis Property Proteins Proteolysis Radiation Safety Series Small Business Technology Transfer Research Solubility Source Stress Structure Structure-Activity Relationship Therapeutic Therapeutic Agents Therapeutic Index Translations acute myeloid leukemia cell antileukemic activity aqueous base cancer therapy chemotherapy clinically relevant commercialization compound 30 conventional therapy design experience high risk improved improved outcome in vivo inhibition of autophagy inhibitor lead candidate leukemia treatment mouse model new therapeutic target novel novel therapeutic intervention patient derived xenograft model pharmacokinetics and pharmacodynamics programs research clinical testing response survival outcome targeted agent targeted treatment therapeutic target therapy resistant tumor progression

项目摘要

Project Summary/Abstract Lysosomal proteolysis facilitates the turnover of organelles and selected long-lived proteins and is a critical regulator of cellular homeostasis. Its aberrant activation promotes drug resistance and cancer progression by generating alternative sources of survival sustaining metabolic fuel to cells that are stressed by hypoxia, radiation, chemotherapy, and targeted agents. Despite its clear potential as a therapeutic target, no intentionally designed targeted inhibitors of lysosomal function have been FDA approved to date. We recently generated a series of novel orally available lysosomal disrupting agents with favorable safety profiles and single agent therapeutic activity. Our first lead hit is active against acute myeloid leukemia (AML) cells with high-risk features and augments the efficacy of azacitidine to significantly extend overall survival in mouse models of AML. Our major goal is to use medicinal chemistry approaches to optimize its pharmacologic properties to develop a novel lysosomal proteolysis inhibitor that can be commercialized for the treatment of patients with AML and other diseases where aberrant pathway activity contributes to pathogenesis.

项目摘要/摘要溶酶体蛋白分解促进细胞器和选定的长寿蛋白的周转，是一个关键的细胞内稳态的调节器。它的异常激活通过以下途径促进耐药和癌症进展为受到低氧压力的细胞提供维持代谢燃料的替代生存来源，放射治疗、化疗和靶向治疗。尽管它作为治疗目标的潜力很明显，但并不是故意的到目前为止，设计的溶酶体功能靶向抑制剂已获得FDA批准。我们最近生成了一个具有良好安全性和单一药剂的新型口服溶酶体干扰剂系列治疗活动。我们的第一个铅打击是针对具有高危特征的急性髓系白血病(AML)细胞并增强了阿扎替丁的疗效，显著延长了急性髓细胞白血病小鼠模型的总生存期。我们的主要目标是利用药物化学方法来优化其药理性质，以开发一种新的可商业化治疗急性髓系白血病和其他疾病的溶酶体蛋白分解抑制剂异常通路活动导致发病机制的疾病。