Novel small molecule USP7 Inhibitors for p53 activation and cancer therapy

用于 p53 激活和癌症治疗的新型小分子 USP7 抑制剂

• 批准号: 10321531
• 负责人: Wei Gu
• 金额: $ 36.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321531
• 关键词: Address; Biological Assay; Cancer Patient; Clinical Data; Clinical Trials; Dose-Limiting; Down-Regulation; Drug resistance; Event; Exhibits; Genotoxic Stress; Goals; Human; Immunity; Immunotherapy; In Vitro; MDM2 gene; Malignant Neoplasms; Mediating; Mutate; Mutation; Neuroblastoma; Normal tissue morphology; PD-1 pathway; PD-1/PD-L1; Pathway interactions; Patients; Peptides; Proteins; Publishing; Resistance; Role; Signal Transduction; Solubility; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Tumor Suppression; Validation; antitumor effect; cancer cell; cancer therapy; dosage; high throughput screening; in vivo; inhibitor; mouse model; new therapeutic target; novel; overexpression; programmed cell death ligand 1; restoration; small molecule; small molecule inhibitor; therapeutically effective; tumor; tumor growth; tumorigenesis

Project Summary: The long-term objective of this project is to develop a novel targeted therapy for human cancers by reactivating the tumor suppression pathways. Although p53 is frequently mutated in almost 50% of human cancers, many human tumors retain wild-type p53 but its activities are downregulated through multiple mechanisms. Inactivation of Mdm2 is a validated approach for the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of highly potent small-molecule inhibitors and peptides that inhibit the MDM2–p53 interaction (also called Mdm2 inhibitors) have been successfully developed and validated in vitro, and several of these Mdm2 inhibitors have been moved to human clinical trials for in vivo validation. Nevertheless, some serious challenges remain to be addressed. The major issue is the dose-limiting toxicity because of low efficacy and severe toxicity to normal tissues with increasing dosage of these Mdm2 inhibitors. Moreover, emergence of p53 mutations in cancer patients developed highly resistance after the initial treatment with Mdm2 inhibitors. Thus, additional cancer targets aiming at this pathway are clearly needed for more effective therapeutic purpose. In this application, we plan to characterize novel small molecule USP7 inhibitors in activating p53 and cancer therapy. The deubiquitinase USP7 (also called HAUSP) was one of the first deubiquitinases (DUBs) that exhibit a specific role in regulating protein stability in vivo. Previous studies from our lab and others demonstrated that inhibition of USP7 leads to p53 activation by destabilizing both Mdm2 and Mdmx. Notably, USP7 inhibitors are also able to induce p53-independent tumor suppression functions in vivo. For example, we identified N-Myc, a major driver in neuroblastoma tumorigenesis as a critical target for USP7. Recently, we discovered PD-L1 as another important target of USP7. Taken together, these studies reveal that USP7 inhibitors have better efficacy because USP7 inhibition activates p53-mediated tumor suppression by downregulating both Mdm2 and Mdmx and also induces p53-independent tumor growth suppression by destabilizing N-Myc and PD-L1. Moreover, the tumors with high levels of N-Myc or PD-L1 may not develop drug resistance even when the p53 gene is mutated. The major hypothesis to be tested here is whether USP7 inhibitors are more effective and better therapeutic agents for the treatment of human cancers. In Aim 1, we will further characterize novel USP7 inhibitors obtained from our high-through-put screening assays in suppressing tumor growth through both p53 activation and N-Myc destabilization in human neuroblastomas. In Aim 2, we will examine whether the USP7 inhibitor is able to promote immunotherapy by downregulating PD-L1 in human cancer cells.

项目摘要： 这个长期目标 重新激活肿瘤的呼吸途径。 癌症，许多人类肿瘤保留了野生型p53，但活动是通过多重元素下降的 机制。 p53通过将近二十年的努力重新激活p53肿瘤功能。 高度有效的小分子抑制剂和肽的MDM2-P53相互作用（也称为MDM2） 抑制剂）已成功开发和验证 被转移到人体临床试验中进行体内验证。 解决的主要问题是剂量限制的毒性，因为效力低下 这些MDM2抑制剂的剂量增加。 在用MDM2抑制剂进行初始治疗后，患者产生了高度的抗性 在此应用程序中，针对途径的目标显然需要更多的治疗目的。 计划在激活p53和癌症治疗中表征新型的小分子USP7抑制剂 去泛素酶USP7（也称为HAUSP）是表现出Apecific角色的第一批去泛素性（DUBS）之一 在调节体内蛋白质的稳定性方面。 USP7通过破坏MDM2和MDMX的稳定而导致p53。 例如，诱导p53非依赖性肿瘤在体内抑制。 在神经母细胞瘤作为USP7的关键靶标中，我们发现了PD-L1。 USP7的重要目标。 USP7抑制作用通过下调MDM2和MDMX，激活p53介导的肿瘤抑制 通过破坏N-YC和PD-L1的稳定性，诱导p53独立的肿瘤生长 在p53基因被突变的情况下，高水平的N-YC或PD-L1也不会产生耐药性 这里要检验的主要假设是USP7抑制剂是有效的治疗剂 为了治疗AIM 1的人类癌症。 我们通过p53激活和N-MYC抑制肿瘤生长的高通道筛查测定法 在AIM 2中，人类神经母细胞瘤的稳定，我们将检查USP7继承者是否能够。 通过下调人类癌细胞中的PD-L1来促进免疫疗法。