Novel Small Molecule MDM2 Inhibitors for Pancreatic Cancer Therapy

项目描述（由申请人提供）：本项目的长期目标是开发针对人类胰腺癌（胰腺导管腺癌，PDA）的新型靶向治疗方法。PDA是一种生存率低、生存时间短的致命性疾病。目前的全身治疗对PDA患者只有边际效益。目前迫切需要开发有效、安全的治疗方法。肿瘤抑制因子（如p53）的缺失和/或癌基因(如MDM2和？-catenin)与PDA患者的耐药和预后不良有关。致癌基因MDM2是p53的负调节因子，已被认为是癌症治疗的有效分子靶点。迄今为止，大多数MDM2的小分子抑制剂（SMIs）被设计为阻断MDM2-p53结合，重新激活p53功能。然而，大多数PDA携带突变的p53和高水平的MDM2；这些MDM2 SMIs预计对PDA的疗效很低或没有疗效。因此，迫切需要设计出新的MDM2 SMIs，能够直接作用于MDM2并发挥其抗癌活性，而不受p53状态的影响。基于这一新的概念框架，申请人设计了一系列新颖的、高选择性的MDM2 SMIs，即1-芳基和1-杂芳基吡啶[b]吲哚衍生物，并生成了初步数据，为进一步开发作为PDA治疗新疗法的先导化合物提供了基础。这些SMIs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、体内功效和最小的宿主毒性。在研究其作用机制时，申请人发现了SP141的第二个靶点：抑制？-catenin在PDA细胞中的表达及其活化活性。在本提案中，申请人将验证SP141是治疗人PDA的一种新的有效和安全的治疗剂，并通过靶向MDM2和？-catenin发挥其抗PDA活性的中心假设。提出了四个假设驱动的特定目标：1)在各种PDA模型中证明SP141的体内功效，包括原位、转基因和原发肿瘤衍生模型；2)证明靶向MDM2是sp141介导的抗pda活性的主要作用机制；3)阐明的作用？-catenin抑制SP141介导的抗癌活性；4)在pda相关模型中表征SP141的药理学和毒理学特性。在完成这些拟议的研究后，预期的结果将提供有关SP141的治疗效果和安全性的信息，并验证针对MDM2和？-连环蛋白在PDA。预计该项目将产生新的PDA治疗临床候选药物，这将对患者护理和公众健康产生重大影响，并且机制研究将更多地阐明MDM2和？-catenin在PDA发生、进展和治疗中的作用。

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.