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: 8630870
• 负责人: WILLIAM G HAWKINS
• 金额: $ 36.01万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630870
• 关键词: Apoptosis; BCL2 gene; Binding; Cancer Etiology; Cancer Patient; Cell Death; Cells; Characteristics; Chemicals; Clinical; Clinical Trials; 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; Medicine; 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 therapy; cancer type; caspase-3; caspase-9; chemical synthesis; chemotherapy; cost; cytotoxic; design; drug candidate; drug development; human BIRC4 protein; human FRAP1 protein; 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; 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（由申请人提供）：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疾病。我们的研究目标是开发治疗胰腺癌的新疗法。Sigma-2 （S2）配体是一种小分子，作为显像剂正在临床研究中，因为它们的受体在胰腺癌中过度表达，这就是它们选择性地定位于这些肿瘤的原因。此外，S2配体被用作治疗药物，因为它们具有导致癌症选择性细胞死亡的内在能力。sigma-2配体的快速和肿瘤选择性摄取机制及其固有的杀伤能力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通过外源性和内在凋亡途径控制细胞凋亡的诱导。最近的x射线晶体学和核磁共振研究已经确定了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sigma-2配体偶联到SMAC模拟物的初步数据显示了对胰腺癌细胞的强大杀伤作用。在这里，我们提出了几种新的SMAC模拟物与sigma-2配体结合的合成和功能分析，最终目标是选择最佳候选药物用于胰腺腺癌患者的I期临床试验。我们假设，通过与sigma-2配体的化学连接，肿瘤选择性靶向SMAC模拟物将证明在胰腺腺癌的治疗中是有效的。在Aim 1中，我们提出了一系列新的S2/Smac偶联物的合成和体外表征，主要关注它们诱导肿瘤细胞凋亡的能力。在Aim 2中，我们将评估我们目前的S2/Smac偶联物和前几个新化合物在体内选择性靶向和杀死胰腺癌的能力。总之，我们在这里提出了一个癌症选择性，sigma-2介导的共递送诱导凋亡货物的新概念。一旦进入细胞，这些药物偶联物通过两个部分的联合活性介导增强的杀伤（双结构域治疗）。因此，递送剂的细胞毒性活性随着其货物的信号通路而增强。这个新概念代表了一个创新的机会，为未来的小分子药物的发展与双重功能结合在一个单一的试剂。