SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER

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 例新发病例，死亡率在所有癌症中排名第四。我们研究工作的目标是开发治疗胰腺癌的新疗法。 Sigma-2 (S2) 配体是作为显像剂正在进行临床研究的小分子，因为它们的受体在胰腺癌中过度表达，这就是它们选择性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伤能力相结合，使 sigma-2 配体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 的激活来抑制细胞凋亡的关键分子。因此，XIAP 通过外在和内在细胞凋亡途径控制细胞凋亡的诱导。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 模拟物缀合的 sigma-2 配体的初步数据显示出对胰腺癌细胞的强大杀伤作用。在这里，我们提出了几种与 sigma-2 配体缀合的新型 SMAC 模拟物的合成和功能分析，最终目标是为胰腺癌患者的 I 期临床试验选择最佳候选药物。我们假设通过与 sigma-2 配体的化学连接对 SMAC 模拟物进行肿瘤选择性靶向将被证明在胰腺癌的治疗中有效。 在目标 1 中，我们提出了一系列新型 S2/Smac 缀合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。在目标 2 中，我们将评估我们当前的 S2/Smac 缀合物和前几种新化合物在体内选择性靶向和杀死胰腺癌的能力。 总之，我们在此提出了癌症选择性、sigma-2 介导的细胞凋亡诱导货物共同递送的新概念。一旦进入细胞，这些药物缀合物通过两个部分的联合活性（双域治疗）介导增强杀伤作用。因此，递送剂的细胞毒活性随着其货物的信号传导途径而增强。这一新概念为未来开发具有双重功能的单一试剂中的小分子药物提供了创新机会。

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.