Small molecules targeting RuvBL complex for triple negative breast cancer

靶向 RuvBL 复合物的小分子治疗三阴性乳腺癌

基本信息

批准号：
10751401
负责人：
Bingbing Li
金额：
$ 60.11万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751401
关键词：
ATP phosphohydrolase ATR gene BRCA mutations Binding Binding Proteins Biological Biological Availability Breast Cancer Cell Breast Cancer Model Cell Line Cell Survival Cell physiology Cells Complementary DNA Complex DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA lesion DNA replication fork Data Defect Double Strand Break Repair Drug Kinetics Epidermal Growth Factor Receptor Estrogen Receptors Evaluation Excision Genotoxic Stress Goals Government Human Ionizing radiation Lead Malignant Neoplasms Molecular Mus Mutate Nonhomologous DNA End Joining Normal Cell Oncogenes Pathway interactions Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Poly(ADP-ribose) Polymerase Inhibitor Pre-Clinical Model Process Progesterone Receptors Prognosis Property Proteins Publishing Reactive Oxygen Species Research Resistance Site Structure Subgroup TP53 gene Therapeutic Therapeutic Agents Toxic effect Xenograft procedure ataxia telangiectasia mutated protein brca gene cancer subtypes chemoproteomics course development druggable target genome integrity homologous recombination improved in vitro activity in vivo inhibitor lead optimization malignant breast neoplasm new therapeutic target novel novel lead compound novel therapeutics overexpression p53-binding protein 1 patient derived xenograft model protein complex repaired replication stress resistance mechanism response small molecule small molecule inhibitor triple-negative invasive breast carcinoma tumor

项目摘要

Abstract The goal of this project is to develop small molecule modulators of RuvBL1/L2 complex as potential therapies for triple negative breast cancer (TNBC) by targeting DNA double-strand breaks (DSB) repair pathways. TNBC is a subgroup of breast cancer and is molecularly characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) or HER2 (human epidermal growth factor receptor 2) amplification. DNA replication stress and reactive oxygen species are prevalent in TNBC cells due to activation of various oncogenes. Thus, TNBC cells constantly generate DSBs. In order for the TNBC cells to survive, these lethal DSBs must be repaired. Accordingly, over the course of development of cancer, TNBC cells have co-evolved efficient DSB repair mechanisms that protect them from the endogenous lethal DSBs. Therefore, targeting DNA repair pathways has been proposed as a potentially powerful strategy to develop novel therapeutics for TNBC. By exploiting this unique feature of endogenous DSBs prevalent only in TNBC cells, such therapeutics can offer selective toxicity to TNBC cells without harming normal cells. We recently identified a novel small molecule lead compound to target RuvBL1/L2 to inhibit DSB repair in TNBC cells. In this application, we propose to further develop this small molecule lead compound for the treatment of TNBC with 3 specific aims. In aim 1, we will study the mechanism of action of this novel lead compound. In aim 2, we will optimize this lead compound using different medicinal chemistry strategies. In aim 3, we will investigate the optimized compounds' anti-TNBC efficacy in different preclinical models alone and in combination with PARP inhibitors.

抽象的该项目的目标是开发 RuvBL1/L2 复合物的小分子调节剂作为潜在的疗法通过靶向 DNA 双链断裂 (DSB) 修复途径治疗三阴性乳腺癌 (TNBC)。三全国广播公司是乳腺癌的一个亚组，其分子特征是缺乏雌激素受体表达 (ER)、孕激素受体 (PR) 或 HER2（人表皮生长因子受体 2）扩增。脱氧核糖核酸由于各种激活因子的激活，复制应激和活性氧在 TNBC 细胞中普遍存在。癌基因。因此，TNBC 细胞不断产生 DSB。为了让 TNBC 细胞生存，这些致命的细胞 DSB 必须修复。因此，在癌症的发展过程中，TNBC 细胞共同进化有效的 DSB 修复机制，保护它们免受内源性致命 DSB 的侵害。因此，针对 DNA 修复途径已被提议作为开发新疗法的潜在强大策略。 TNBC。通过利用仅在 TNBC 细胞中普遍存在的内源性 DSB 的这一独特特征，此类疗法可以对 TNBC 细胞产生选择性毒性，而不伤害正常细胞。我们最近发现了一个新颖的小分子先导化合物靶向 RuvBL1/L2，抑制 TNBC 细胞中的 DSB 修复。在这个应用程序中，我们建议进一步开发这种小分子先导化合物来治疗 TNBC，有 3 个具体目标。在目标 1 中，我们将研究这种新型先导化合物的作用机制。在目标 2 中，我们将对此进行优化使用不同药物化学策略的先导化合物。在目标 3 中，我们将研究优化的化合物单独和与 PARP 抑制剂组合在不同临床前模型中的抗 TNBC 功效。