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：
10444602
负责人：
DAQING WU
金额：
$ 54.32万
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/10444602
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 Pharmacology and Toxicology Phenotype Polycomb Pre-Clinical Model Property Prostate Cancer therapy Protein Kinase Reader Research Resistance S phase Safety Signal Transduction Specificity Stat2 protein Stat3 protein Testing Texas Therapeutic Toxic effect Translating Translational Research Universities Work Xenograft Model absorption advanced prostate cancer analog anticancer activity base castration resistant prostate cancer chemotherapy clinical development design docetaxel drug development drug discovery good laboratory practice improved in vivo in vivo evaluation inhibitor innovation lead optimization mortality novel novel strategies 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cast割前列腺癌（PCA）的一线化学疗法，这是主要的 PCA死亡率的原因。不幸的是，在大多数情况下，PCA会产生多西他赛的抵抗力，并继续进步，无法治愈。我们最近的研究（Theranostics，2021年5月8日； 11：6873-6890）有力的证据表明，化学耐药的PCA细胞依赖于活性的EED-EZH2-STAT3-SKP2- ABCB1/survivin信号传导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抑制剂相互作用可有效克服化学抗性和消除致命的PCA细胞。在AIM 1中，我们将进行新型EED的合理设计和化学优化抑制剂。总共设计和合成了200个新的化学实体。在AIM 2中，我们将验证化学耐药性PCA细胞中电铅的作用机理。我们将识别体内和体内新的EED EED抑制剂对化学耐药性PCA的活性在多个异质临床前模型化学耐药性PCA。在AIM 3中，我们将进行良好的实验室实践（GLP）和非GLP研究评估铅化合物的药物样性能，包括药代动力学，吸收，分布，代谢和排泄（ADME），单剂量毒性和安全药理学。成功完成该项目，我们期望确定1〜2个可申请的铅化合物并将其提高到进一步的临床前和临床发展。总体目标是将我们的基础研究转化为有效且安全的PCA治疗，因此使患者受益并改善临床结果。