Full Project 2

Pin1是一种顺式-反式Prolyl异构酶，控制Pro介导的磷酸化信号转导事件，即 在胰腺癌细胞和与癌症相关的成纤维细胞中均过表达。Pin1的过度表达是一个主要的 肿瘤发生的贡献者，激活几种癌蛋白，包括KRAS途径中的蛋白，以及 同时使几个肿瘤抑制因子失活。利用遗传学和药理学的最新研究 抑制物显示Pin1调节关键的致癌途径。重要的是，Pin1促进了 免疫抑制/耐药TME，通过上调PD-L1(程序性细胞死亡受体-1) 化疗药物吉西他滨经常用于胰腺癌的一线治疗。PIN1也会开车 吉西他滨摄取转运体ENT1(均衡性核)的降解导致化疗耐药 转运蛋白-1)在肿瘤细胞和癌症相关的成纤维细胞中都有表达。因此，Pin1抑制剂的发展 可以增加胰腺癌对化疗和免疫治疗的敏感性。博士的实验室。 Pellecchia(加州大学河滨分校；UCR)已经开发出最初的Pin1抑制剂，前景看好 药代动力学特性。为此，Pellecchia博士使用了一种基于组合的药物发现策略 生物物理方法包括1)药物化学，2)核磁共振波谱，3)X射线结晶学(Dr。 Blaha，UCR)和4)变性热位移测量。这种基于结构的设计方法用于 衍生创新的共价Pin1靶向药物，导致Pin1在胰腺细胞系中的降解。引导式 根据我们的资源和初步数据，我们建议UCR和CoH合作1)优化和2) 开发一种有效和选择性的PIN1抑制剂用于治疗胰腺癌。目标1将设计、合成、 并反复优化新型、类药物的PIN1靶向剂。目标2将研究作用机制和 最有希望的药物在胰腺癌细胞和动物模型中的疗效。我们将评估 精制制剂在小鼠体内的药代动力学特性(Horne博士和CoHCCC共享资源)，并测试其 胰腺癌动物模型(Horne博士、Raoof博士、Coh博士)的疗效，包括原位、患者来源 异种移植和胰腺癌转基因小鼠模型。

PIN1 is a cis-trans prolyl isomerase that controls proline-mediated phosphorylation signaling events that is overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major contributor to tumorigenesis, activating several oncoproteins, including proteins in the KRAS pathway, and simultaneously inactivating several tumor suppressors. Recent studies using genetic and pharmacological inhibitors show that PIN1 regulates key oncogenic pathways. Importantly, PIN1 promotes an immunosuppressive/treatment-resistant TME, by up-regulating PD-L1 (programmed cell-death receptor-1) The chemotherapy drug, gemcitabine, is frequently used in front-line treatment of pancreatic cancer. PIN1 also drives chemotherapy-resistance by degrading the gemcitabine uptake-transporter, ENT1 (equillabrative nuclear transporter-1) both in tumor cells and cancer-associated fibroblasts. Hence, the development of PIN1 inhibitors could increase sensitivity of pancreatic cancer to both chemotherapy and immunotherapy. The laboratory of Dr. Pellecchia (University of California Riverside; UCR) has developed initial PIN1 inhibitors that have promising pharmacokinetic properties. To do this, Dr. Pellecchia used a drug discovery strategy based on a combination of biophysical methods including 1) medicinal chemistry 2) NMR spectroscopy, 3) X-ray crystallography (Dr. Blaha, UCR) and 4) denaturation thermal shift measurements. This structure-based design approach used to derive innovative covalent PIN1 targeting agents that cause degradation of PIN1 in pancreatic cell lines. Guided by our resources and preliminary data, we propose a collaboration between UCR and CoH to 1) optimize and 2) develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthetize, and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and efficacy of most promising agents in cellular and animal models of pancreatic cancer. We will assess the pharmacokinetics properties (Dr. Horne and CoHCCC shared resources) of refined agents in mice and test their efficacy in animal models of pancreatic cancer (Dr. Horne, Dr. Raoof, CoH) including orthotopic, patient derived xenografts, and transgenic mouse models of pancreatic cancer.