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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.

多西他赛是转移性去势抵抗性前列腺癌（PCa）的一线化疗药物， PCa死亡原因不幸的是，在大多数情况下，PCa发展为多西他赛耐药，并继续进步，无药可救。我们最近的研究（Theranostics，2021年5月8日; 11：6873-6890）提供了强有力的证据表明，化学抗性PCa细胞依赖于活性EED-EZH 2-Stat 3-SKP 2- ABCB 1/生存素信号传导以存活并逃避标准化疗。在这个R 01项目中，我们假设靶向EED-EZH 2与新型EED抑制剂的相互作用可有效克服化学抗性，消除致命的前列腺癌细胞。在目标1中，我们将对新型电火花点火装置进行合理设计和化学优化抑制剂的总共将设计和合成200种新的化学实体。在目标2中，我们将验证潜在的先导化合物在耐药前列腺癌细胞中的作用机制。我们将在体外和体内鉴定新的EED抑制剂在多个异质性临床前模型中对耐药PCa的活性化疗耐药前列腺癌。在目标3中，我们将开展药物非临床研究质量管理规范（GLP）和非GLP研究，评价先导化合物的类药物性质，包括药代动力学、吸收、分布，代谢和排泄（ADME）、单次和重复给药毒性和安全性药理学。与成功本项目完成后，我们预计将发现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。首要目标是将我们的基础研究转化为有效和安全的治疗致死性PCa，从而使患者受益并改善临床结局。