SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER

SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡

• 批准号: 8879063
• 负责人: WILLIAM G HAWKINS
• 金额: $ 37.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879063
• 关键词: Apoptosis; BCL2 gene; Binding; Cancer Etiology; Cancer Patient; Cell Death; Cells; Characteristics; Chemicals; Clinical; Data; Defect; Development; Diagnosis; Disease; Evaluation; Excision; Family; Future; Goals; Human; Image; In Vitro; Individual; Induction of Apoptosis; Inhibition of Apoptosis; Investigation; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane; Molecular Target; Pancreatic Adenocarcinoma; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Positioning Attribute; Progesterone Receptors; Proto-Oncogene Proteins c-akt; Reagent; Refractory; Research; Resistance; Series; Signal Pathway; Site; Technology; Testing; Therapeutic; Toxic effect; United States; Validation; X-Ray Crystallography; advanced disease; anti-cancer therapeutic; base; cancer imaging; cancer type; caspase-3; caspase-9; chemical synthesis; chemotherapy; clinical investigation; cost; cytotoxic; design; drug candidate; drug development; human BIRC4 protein; human FRAP1 protein; imaging agent; in vitro testing; in vivo; inhibitor-of-apoptosis protein; inhibitor/antagonist; innovation; killings; member; mimetics; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; pancreatic cancer cells; peptidomimetics; personalized cancer therapy; personalized medicine; receptor; sigma-2 receptor; small molecule; tumor; uptake

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease, with an estimated 43,140 new cases in the United States in 2010, and represents the fourth highest mortality overall amongst all cancers. The objective of our research efforts is to develop novel therapeutics for the treatment of pancreatic cancer. Sigma-2 (S2) ligands are small molecules that are under clinical investigation as imaging agents because their receptors are overexpressed in pancreatic cancer, which is the reason why they selectively localize to these tumors. In addition, S2 ligands are pursued as therapeutics because they have an intrinsic ability to cause cancer-selective cell death. The rapid and cancer-selective uptake mechanism in combination with their intrinsic killing capacity puts sigma-2 ligands into a strategic position for drug development evaluations. XIAP is a key molecule for the inhibition of apoptosis by blocking the activation of caspases-3/7 and caspase-9. As such, XIAP controls induction of apoptosis through the extrinsic as well as the intrinsic apoptosis pathway. Recent X-ray crystallography and NMR studies have identified the structural interactions between XIAP and its natural inhibitor, SMAC. Of note, preliminary data using a sigma-2 ligand conjugated to a SMAC mimetic showed robust killing of pancreatic cancer cells. Here, we propose the synthesis and functional analysis of several novel SMAC mimetics conjugated to sigma-2 ligands with the ultimate goal of selecting the best drug candidate(s) for a phase I clinical trial in patients with pancreatic adenocarcinoma. We hypothesize that tumor-selective targeting of SMAC mimetics through chemical linkage to sigma-2 ligands will prove efficacious in the treatment of pancreatic adenocarcinoma. In Aim 1, we propose the synthesis and in vitro characterization of a series of novel S2/Smac conjugates focusing primarily on their ability to induce tumor cell apoptosis. In Aim 2, we will assess our current S2/Smac conjugate and the top few new compounds for their ability to selectively target and kill pancreatic cancers in vivo. In summary, we present here a novel concept for the cancer-selective, sigma-2- mediated co-delivery of apoptosis-inducing cargo. Once inside the cell, these drug conjugates mediate enhanced killing via the combined activities of both moieties (dual-domain therapeutics). As a result, the cytotoxic activity of the delivery agent is augmented following the signaling pathway of its cargo. This new concept represents an innovative opportunity for the development of future small molecule drugs with dual functionality combined in a single reagent.

描述(申请人提供)：胰腺癌是一种毁灭性的疾病，2010年美国估计有43,140例新病例，是所有癌症中死亡率第四高的。我们的研究目标是开发治疗胰腺癌的新疗法。Sigma-2(S2)配体是临床研究中的显像剂，因为它们的受体在胰腺癌中过表达，这就是它们选择性地定位于这些肿瘤的原因。此外，S2配体作为治疗药物受到追捧，因为它们具有导致癌症选择性细胞死亡的内在能力。Sigma-2配体的快速和癌症选择性摄取机制与其内在的杀伤能力相结合，使其在药物开发评估中处于战略地位。XIAP是通过阻断caspase-3/7和caspase-9的激活而抑制细胞凋亡的关键分子。因此，XIAP通过外在和内在的凋亡途径控制细胞凋亡的诱导。最近的X射线结晶学和核磁共振研究证实了XIAP与其天然抑制剂Smac之间的结构相互作用。值得注意的是，使用连接到Smac模拟物的sigma-2配体的初步数据显示，对胰腺癌细胞的杀伤力很强。在这里，我们提出了几个新的Smac类似物的合成和功能分析，最终目的是选择最佳候选药物(S)用于胰腺癌患者的I期临床试验。我们推测，通过Smac类似物与Sigma-2配体的化学连接，肿瘤选择性靶向将被证明在治疗胰腺癌方面是有效的。在目标1中，我们提出了一系列新型S2/Smac结合物的合成和体外表征，主要集中在它们诱导肿瘤细胞凋亡的能力上。在目标2中，我们将评估我们目前的S2/Smac结合物和几个最新的化合物在体内选择性靶向和杀死胰腺癌的能力。综上所述，我们在这里提出了一个新的概念，用于癌症选择性的，sigma-2介导的共传递诱导凋亡的货物。一旦进入细胞，这些药物结合物通过两个部分的联合作用(双域疗法)介导增强杀伤。因此，递送剂的细胞毒活性随着其货物的信号通路而增强。这一新概念为未来在单一试剂中结合双功能的小分子药物的开发提供了一个创新的机会。