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

• 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
• 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

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.

摘要 本研究的目的是开发RuvBL 1/L2复合物的小分子调节剂作为潜在的治疗药物 通过靶向DNA双链断裂（DSB）修复途径治疗三阴性乳腺癌（TNBC）。TNBC 是乳腺癌的一个亚群，其分子特征是缺乏雌激素受体的表达 (ER)孕酮受体（PR）或HER 2（人表皮生长因子受体2）扩增。DNA 复制应激和活性氧物质在TNBC细胞中普遍存在，这是由于多种细胞因子的激活。 致癌基因因此，TNBC细胞不断产生DSB。为了使TNBC细胞存活，这些致命的 必须修复DSB。因此，在癌症发展过程中，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死DSB的伤害。因此，针对 DNA修复途径已被提出作为开发新的治疗方法的潜在的强大策略，用于 TNBC。通过利用仅在TNBC细胞中普遍存在的内源性DSB的这种独特特征， 可以对TNBC细胞提供选择性毒性而不伤害正常细胞。我们最近发现了一种新的小 分子引导化合物靶向RuvBL 1/L2以抑制TNBC细胞中的DSB修复。在本申请中，我们 建议进一步开发这种小分子先导化合物，用于治疗TNBC，具有3个特定目标。 在目的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，我们将优化这一点 先导化合物使用不同的药物化学策略。在目标3中，我们将研究优化的 图4显示了化合物在不同临床前模型中单独和与PARP抑制剂组合的抗TNBC功效。