Novel Small Molecule MDM2 Inhibitors for Pancreatic Cancer Therapy

用于胰腺癌治疗的新型小分子 MDM2 抑制剂

• 批准号: 8721161
• 负责人: RUIWEN ZHANG
• 金额: $ 49.7万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721161
• 关键词: Adenocarcinoma Cell; Antineoplastic Agents; Apoptosis; Binding; Biology; Cancer Etiology; Cancer Model; Cell Cycle Progression; Clinical; Clinical Research; Clinical Trials; Computer Assisted; Data; Development; Disease; Drug Design; Drug Kinetics; Effectiveness; Erlotinib; Fluorouracil; Future; Genetic; Goals; Human; In Vitro; Indoles; Lead; Link; MDM2 gene; Malignant neoplasm of pancreas; Mediating; Medical; Modeling; Molecular; Molecular Target; Neoplasm Metastasis; Oncogenes; Oncogenic; Pancreatic Ductal Adenocarcinoma; Patient Care; Patients; Pharmacology and Toxicology; Play; Primary Neoplasm; Principal Investigator; Property; Public Health; Resistance; Role; Safety; Series; Solid; Structure; Survival Rate; Systemic Therapy; Testing; Therapeutic Agents; Time; Toxic effect; Transactivation; Transgenic Organisms; Treatment Efficacy; Tumor Suppressor Proteins; Tumor-Derived; Validation; anticancer activity; base; cancer therapy; cell growth; clinically relevant; cytotoxicity; design; drug sensitivity; gemcitabine; high throughput screening; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; mutant; novel; novel therapeutics; outcome forecast; overexpression; pre-clinical; programs; public health relevance; response; small molecule; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop novel targeted therapy for human pancreatic cancer (pancreatic ductal adenocarcinoma, PDA). PDA is a devastating disease with low survival rate and short survival time. The current systemic therapy has only marginal benefit to PDA patients. There is an urgent need for the development of effective and safe therapy for PDA. The loss of tumor suppressor (e.g., p53) and/or the overexpression of oncogenes (e.g., MDM2 and ?-catenin) have been linked to resistant to treatment and poor prognosis in PDA patients. The oncogene MDM2 is a negative regulator of p53 and has been suggested to be a valid molecular target for cancer therapy. Up to date, the majority of small molecule inhibitors (SMIs) of MDM2 have been designed to block the MDM2-p53 binding, reactivating the p53 function. However, the majority of PDA harbors mutant p53 and has high levels of MDM2; these MDM2 SMIs are expected to have low or no efficacy against PDA. Therefore, it is highly desirable to design novel MDM2 SMIs that have direct effects on MDM2 and exert their anticancer activity, independent of p53 status. Based on this new conceptual framework, the applicants have designed a series of novel, highly selective MDM2 SMIs, i.e. 1-aryl and 1- heteroaryl pyrido[b]indole derivatives and generated preliminary data to provide a basis for further development of the lead compounds as novel therapeutics for PDA treatment. These SMIs directly bind to MDM2, induce MDM2 degradation, inhibit cell growth, and induce apoptosis in PDA cells. One of the lead compounds, SP141, has significant in vitro activity, in vivo efficacy, and minimal host toxicity. When investigating its mechanisms o action, the applicants discovered a secondary target of SP141: inhibiting ?-catenin expression and its transactivation activity in PDA cells. In this proposal, the applicants will test the centrl hypothesis that SP141 is a novel effective and safe therapeutic agent for the treatment of human PDA and exerts its anti-PDA activity through targeting both MDM2 and ?-catenin. Four hypothesis-driven specific aims are proposed: 1) to demonstrate the in vivo efficacy of SP141 in various PDA models, including orthotopic, transgenic, and primary tumor-derived models; 2) to demonstrate that targeting MDM2 is the major mechanism of action for SP141-mediated anti-PDA activity; 3) to elucidate the role of ?-catenin inhibition in SP141- mediated anticancer activity; and 4) to characterize the pharmacological and toxicological properties of SP141 in PDA-relevant models. Upon completion of these proposed studies, the anticipated results will provide information on the therapeutic efficacy and safety of SP141 and the validation of the novel drug design strategy of targeting both MDM2 and ?-catenin in PDA. It is expected that this project will generate in a novel clinical candidate for PDA therapy, which would have a major impact on patient care and public health and that the mechanistic studies will shed more lights on the role of MDM2 and ?-catenin in PDA development, progression, and therapy.

描述(申请人提供)：该项目的长期目标是为人类胰腺癌(胰腺导管腺癌，PDA)开发新的靶向治疗方法。动脉导管未闭是一种存活率低、生存时间短的破坏性疾病。目前的系统治疗对PDA患者的益处微乎其微。迫切需要开发有效、安全的PDA治疗方法。肿瘤抑制基因(如P53)的缺失和/或癌基因(如MDM2和β-catenin)的过度表达与PDA患者耐药和预后不良有关。癌基因MDM2是P53的负调控基因，已被认为是癌症治疗的有效分子靶点。到目前为止，大多数MDM2的小分子抑制剂(SMI)都被设计成阻断MDM2与P53的结合，重新激活P53功能。然而，大多数PDA含有突变型p53并具有高水平的MDM2；这些MDM2 SMI预计对PDA的疗效较低或没有效果。因此，设计一种能直接作用于MDM2并发挥其抗癌活性而不依赖于P53状态的新型MDM2 SMI是非常有必要的。基于这一新的概念框架，申请人设计了一系列新的、高选择性的MDM2 SMIs，即1-芳基和1-杂芳基吡啶[b]吲哚衍生物，并产生了初步数据，为进一步开发先导化合物作为治疗PDA的新疗法提供了基础。这些SMI直接与MDM2结合，诱导MDM2降解，抑制细胞生长，诱导PDA细胞凋亡。其中一种先导化合物SP141具有显著的体外活性、体内药效和最小的寄主毒性。在研究其作用机制时，申请人发现了SP141的第二个靶点：抑制？-连环蛋白的表达及其在PDA细胞中的反式激活活性。在这项提案中，申请者将检验CENTIL假设，即SP141是一种治疗人类PDA的新型有效和安全的治疗剂，并通过靶向MDM2和β-连环蛋白发挥其抗PDA活性。提出了四个假说驱动的特定目标：1)证明SP141在各种PDA模型中的体内作用，包括原位、转基因和原发肿瘤来源的模型；2)证明靶向MDM2是SP141介导的抗PDA活性的主要作用机制；3)阐明β-连环蛋白抑制在SP141介导的抗癌活性中的作用；以及4)表征SP141在PDA相关模型中的药理学和毒理学特性。在这些拟议的研究完成后，预期的结果将提供关于SP141的疗效和安全性的信息，以及针对PDA中MDM2和β-连环蛋白的新药设计策略的有效性。预计该项目将产生一种新的PDA治疗的临床候选方案，这将对患者护理和公共健康产生重大影响，机制研究将进一步阐明MDM2和β-catenin在PDA的发生、发展和治疗中的作用。