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Targeting chemoresistant prostate cancer with novel EED inhibitors

使用新型 EED 抑制剂靶向化疗耐药性前列腺癌

基本信息

批准号：
10590661
负责人：
DAQING WU
金额：
$ 46.34万
依托单位：
CLARK ATLANTA UNIVERSITY
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：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590661
关键词：
ABCB1 gene Basic Science Binding Biological Biology Cancer Patient Characteristics Chemicals Chemoresistance Clinical Complex Development Disease Progression Dose Drug Design Drug Kinetics Ectoderm Embryo Enhancers Epigenetic Process Excretory function Goals Growth Homologous Gene In Vitro Interruption Intervention Knowledge Lead Malignant neoplasm of prostate Medical Metabolism Mus NCI Center for Cancer Research Oncogenic Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacology Phenotype Polycomb Pre-Clinical Model Property Prostate Cancer therapy Protein Kinase Qualifying Reader Research Resistance S phase Safety Signal Transduction Specificity Stat2 protein Stat3 protein Testing Texas Therapeutic Toxic effect Toxicology Translating Translational Research Universities Work Xenograft Model absorption advanced prostate cancer analog anticancer activity castration resistant prostate cancer chemotherapy clinical development design docetaxel drug development drug discovery drug synthesis good laboratory practice improved in vivo in vivo evaluation inhibitor innovation lead optimization mortality new chemical entity novel novel strategies pharmacologic pre-clinical preclinical development preclinical efficacy preclinical safety prostate cancer cell prostate cancer model rational design research and development screening small molecule standard of care survivin theranostics therapeutic development

项目摘要

Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PCa), the major cause of PCa mortality. Unfortunately, in most cases PCa develops docetaxel resistance and continues to progress, which has no cure. Our recent studies (Theranostics, 2021, May 8; 11: 6873-6890) have provided strong evidence demonstrating that chemoresistant PCa cells rely on an active EED-EZH2-Stat3-SKP2- ABCB1/survivin signaling to survive and evade standard chemotherapy. In this R01 project, we hypothesize that targeting EED-EZH2 interaction with novel EED inhibitors is effective to overcome chemoresistance and eliminate lethal PCa cells. In Aim 1, we will conduct rational design and chemical optimization of novel EED inhibitors. A total of 200 new chemical entities will be designed and synthesized. In Aim 2, We will validate the mechanism of action of potential leads in chemoresistant PCa cells. We will identify the in vitro and in vivo activities of new EED inhibitors against chemoresistant PCa in multiple, heterogenous preclinical models of chemoresistant PCa. In Aim 3, we will conduct Good Laboratory Practice (GLP) and non-GLP studies to evaluate the drug-like properties of lead compounds, including pharmacokinetics, absorption, distribution, metabolism, and excretion (ADME), single- and repeat-dose toxicity and safety pharmacology. With successful accomplishment of this project, we expect to identify 1~2 patentable lead compounds and advance them into further preclinical and clinical development. The overarching goal is to translate our basic research into an effective and safe treatment for lethal PCa, therefore benefiting patients and improving clinical outcomes.

多西紫杉醇是转移性去势抵抗性前列腺癌（PCa）的一线化疗药物