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.

多西紫杉醇是治疗转移性去势抵抗性前列腺癌 (PCa) 的一线化疗药物，PCa 是主要的癌症 PCa 死亡的原因。不幸的是，在大多数情况下，PCa 会产生多西紫杉醇耐药性并继续进步，但无法治愈。我们最近的研究（Theranostics，2021，5 月 8 日；11：6873-6890）提供了强有力的证据表明，化疗耐药性 PCa 细胞依赖于活性 EED-EZH2-Stat3-SKP2- ABCB1/生存素信号传导以生存并逃避标准化疗。在这个 R01 项目中，我们假设靶向 EED-EZH2 与新型 EED 抑制剂的相互作用可有效克服化疗耐药性消除致命的 PCa 细胞。在目标1中，我们将对新型EED进行合理设计和化学优化抑制剂。总共将设计和合成200种新化学实体。在目标 2 中，我们将验证潜在先导化合物在化疗耐药 PCa 细胞中的作用机制。我们将鉴定体外和体内新型 EED 抑制剂在多种异质临床前模型中对抗化疗耐药 PCa 的活性化疗耐药 PCa。在目标 3 中，我们将开展良好实验室规范 (GLP) 和非 GLP 研究，以评估先导化合物的类药特性，包括药代动力学、吸收、分布、代谢和排泄（ADME）、单剂量和重复剂量毒性和安全药理学。与成功的该项目的完成，我们预计将鉴定出1~2个可申请专利的先导化合物，并将其推进到进一步的临床前和临床开发。总体目标是将我们的基础研究转化为有效且安全地治疗致命性前列腺癌，从而使患者受益并改善临床结果。