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

基本信息

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
项目类别：
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

项目摘要

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，估计在2010年在美国有43,140例新病例，代表了所有癌症中总体上第四高死亡率。我们研究工作的目的是开发用于治疗胰腺癌的新型治疗剂。 Sigma-2（S2）配体是小分子，由于其受体在胰腺癌中过表达，因此正在临床研究中，这就是它们有选择地定位于这些肿瘤的原因。此外，S2配体被视为治疗剂，因为它们具有引起癌症选择性细胞死亡的内在能力。快速和癌症选择性摄取机制与其内在的杀戮能力相结合，使Sigma-2配体成为药物开发评估的战略地位。 XIAP是通过阻断caspase-3/7和caspase-9的激活来抑制凋亡的关键分子。因此，XIAP通过外在以及内在凋亡途径控制凋亡的诱导。最近的X射线晶体学和NMR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，使用与SMAC模拟物结合的Sigma-2配体的初步数据显示胰腺癌细胞的稳健杀死。在这里，我们提出了几种与Sigma-2配体结合的新型SMAC模拟物的合成和功能分析，其最终目标是为胰腺腺癌患者选择最佳药物候选药物（S）。我们假设通过化学连接到Sigma-2配体将SMAC模拟物的肿瘤选择性靶向将有效地治疗胰腺腺癌。在AIM 1中，我们提出了一系列新型S2/SMAC共轭物的合成和体外表征，主要关注其诱导肿瘤细胞凋亡的能力。在AIM 2中，我们将评估当前的S2/SMAC结合物，以及在体内有选择性靶向和杀死胰腺癌的能力的最佳新化合物。总而言之，我们在这里提出了一个新颖的概念，用于癌症选择性，Sigma-2介导的诱导凋亡货物的共同传递。一旦进入细胞，这些药物结合物通过两个部分的联合活性（双域治疗剂）介导了增强的杀戮。结果，在其货物的信号传导途径之后，递送剂的细胞毒性活性得到了增强。这个新概念代表了一种创新的机会，用于开发未来的小分子药物，具有双重功能。