Discovery of Constrained Peptoid Oligomers for Novel Therapy of Multiple Myeloma

描述(申请人提供)：多发性骨髓瘤(MM)是一种侵袭性的血癌形式，每年有超过22,000例新病例。目前的治疗方法是基于抑制蛋白酶体，蛋白酶体是一种执行多种基本细胞活动的多蛋白酶。最重要的是，蛋白酶体负责降解错误折叠和/或不起作用的蛋白质。抑制蛋白酶体会导致细胞死亡，因此，这种酶是癌症治疗的有效靶点。蛋白酶体抑制剂对多发性骨髓瘤特别有效，因为这种癌症已经被证明表达了异常高水平的这种蛋白复合体。不幸的是，针对负责蛋白质降解的蛋白酶体催化部分的先前开发的蛋白酶体抑制剂的耐药性迅速演变，使患者几乎没有替代治疗方法。需要一种新的治疗方法，仍然利用多发性骨髓瘤对蛋白酶体抑制剂的敏感性，但需要一种新的作用机制。为了应对这一挑战，我们建议靶向蛋白酶体的一个不同的亚单位，即19S调节颗粒(RP)。19S RP负责识别并将降解的蛋白质运送到蛋白酶体的催化核心。到目前为止，还没有人19S RP的小分子抑制剂被开发出来。本次培训的目的是通过合成一个大的限制性模拟肽低聚体(CPIO)组合文库，并应用各种方法来确定我们的CPIO的结合能力和活性抑制，从而确定19S RP抑制剂。CPIO文库将利用为多肽和类肽开发的合成技术，但将纳入天然产品中的部分化合物，因为这些化合物通常具有生物活性，并且通常比标准多肽/类肽更有效。我们将产生具有众多立体中心和主干刚性的CPIO，这些特征以前从未被探索过。最初的打击将使用结合分析来确定，以便于针对19S RP快速筛选我们的大型文库。接下来，将测试与19S RP结合的CPIO的酶活性抑制情况。最后，最有效的CPIO抑制剂将在BTH抗性和对蛋白酶体抑制剂敏感的MM细胞系中进行试验，以确定它们诱导细胞死亡的能力。我们预计，我们的新的小分子文库将导致一种 19S RP抑制剂，为MM提供了一种潜在的新治疗方法。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an aggressive form of blood cancer with over 22,000 new cases each year. Current therapies are based upon inhibition of the proteasome, a multi-protein enzyme that performs a multitude of essential cellular activities. Most importantly, the proteasome is responsible for degrading misfolded and/or non-functioning proteins. Inhibition of the proteasome leads to cell death; hence, this enzyme is a valid target for cancer therapy. Proteasome inhibitors are especially effective against MM because this cancer has been shown to express exceptionally high levels of this protein complex. Unfortunately, resistance to the previously developed proteasome inhibitors that target the catalytic portion of the proteasome responsible for protein degradation has evolved rapidly leaving patients with few alternative treatments. A new therapy that still takes advantage of MM's susceptibility to proteasome inhibitors, but that functions by a novel mechanism of action is needed. To address this challenge, we propose to target a different subunit of the proteasome, namely the 19S regulatory particle (RP). The 19S RP is responsible for recognizing and shuttling proteins for degradation to the catalytic core of the proteasome. To date, no small molecule inhibitor of the human 19S RP has been developed. The objective of this training fellowship is to identify a 19S RP inhibitor through the synthesis of a large combinatorial library of constrained peptidomimetic oligomers (CPIOs) and application of assays for determination of the binding ability and activity inhibition of our CPIOs. The CPIO library wil utilize synthetic techniques developed for peptides and peptoids but will incorporate moieties found in natural products since these compounds are often bioactive and are typically much more potent than standard peptides/peptoids. We will generate CPIOs with numerous stereocenters and backbone rigidity, characteristics that have not been previously explored. Initial hits will be determined using a binding assay to facilitate rapid screening of our large library against the 19S RP. Next, CPIOs that bind to the 19S RP will be tested for enzyme activity inhibition. Finally, the most potent CPIO inhibitors will be subjected to MM cell lines, bth resistant and susceptible to proteasome inhibitors, for determination of their ability to induce cel death. We anticipate that our novel library of small molecules will lead to the identification of a 19S RP inhibitor, providing a potential new treatment for MM.