Novel Small Molecule MDM2 Inhibitors for Pancreatic Cancer Therapy

描述（由申请人提供）：本项目的长期目标是开发人胰腺癌（胰腺导管腺癌，PDA）的新型靶向治疗。PDA是一种生存率低、生存时间短的毁灭性疾病。目前的系统治疗对PDA患者只有边际效益。目前迫切需要开发有效和安全的治疗PDA的方法。肿瘤抑制因子的丧失（例如，p53）和/或癌基因的过表达（例如，MDM 2和？-连环蛋白）与PDA患者的治疗抵抗和不良预后有关。癌基因MDM 2是p53的负调节因子，并已被认为是癌症治疗的有效分子靶点。迄今为止，大多数MDM 2的小分子抑制剂（SMI）已被设计成阻断MDM 2-p53结合，重新激活p53功能。然而，大多数PDA携带突变型p53并具有高水平的MDM 2;预计这些MDM 2 SMI对PDA的效力较低或无效力。因此，非常需要设计新的MDM 2 SMI，其对MDM 2具有直接作用并发挥其抗癌活性，而不依赖于p53状态。基于这种新的概念框架，申请人设计了一系列新的、高选择性的MDM 2 SMI，即1-芳基和1-杂芳基吡啶并[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PDA治疗的新疗法提供了基础。这些SMI直接与MDM 2结合，诱导MDM 2降解，抑制细胞生长，并诱导PDA细胞凋亡。先导化合物之一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的次要靶标：抑制？连环蛋白在PDA细胞中的表达及其反式激活活性。在该提案中，申请人将测试中心假设，即SP141是用于治疗人PDA的新型有效且安全的治疗剂，并且通过靶向MDM 2和β-内酰胺酶发挥其抗PDA活性。连环蛋白。提出了四个假设驱动的具体目标：1）证明SP141在各种PDA模型（包括原位、转基因和原发性肿瘤衍生模型）中的体内疗效; 2）证明靶向MDM 2是SP141介导的抗PDA活性的主要作用机制; 3）阐明？SP141介导的抗癌活性中的连环蛋白抑制;和4）在PDA相关模型中表征SP141的药理学和毒理学性质。在完成这些拟议的研究后，预期的结果将提供有关SP141的治疗有效性和安全性的信息，并验证靶向MDM 2和？- PDA中的连环蛋白。预计该项目将产生一种新的PDA治疗临床候选药物，这将对患者护理和公共卫生产生重大影响，并且机制研究将更多地阐明MDM 2和？连环蛋白在PDA发生、发展和治疗中的作用。

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.