Discovery of Constrained Peptoid Oligomers for Novel Therapy of Multiple Myeloma

发现用于多发性骨髓瘤新疗法的受限肽寡聚物

• 批准号: 8717862
• 负责人: Darci J Trader
• 金额: $ 4.99万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717862
• 关键词: Address; Anemia; Antibodies; Binding; Biological; Biological Assay; Biological Factors; Blood; Catalytic Domain; Cell Death; Cell Line; Cell Proliferation; Cell physiology; Cells; Cessation of life; Characteristics; Chemicals; DNA; DNA-Directed RNA Polymerase; Development; Disease; Disease Resistance; Drug Kinetics; Drug resistance; Ensure; Enzymes; Erythrocytes; Exhibits; Fellowship; Future; Gene Mutation; Generations; Goals; Hematopoietic Neoplasms; Human; Inhibitory Concentration 50; Kidney Failure; Lead; Left; Lesion; Libraries; Malignant Neoplasms; Maps; Modification; Multiple Myeloma; Pain; Patients; Peptide Library; Peptides; Peptoids; Pharmaceutical Preparations; Plasma Cells; Predisposition; Property; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Protocols documentation; Resistance; Signaling Molecule; Techniques; Testing; Therapeutic; Therapeutic Agents; Training; Ubiquitin; Validation; Vertebral column; Yeasts; alternative treatment; base; bone; cancer therapy; cancer type; combinatorial; combinatorial chemistry; crosslink; design; enzyme activity; in vivo; inhibitor/antagonist; killings; multicatalytic endopeptidase complex; novel; novel therapeutics; particle; peptidomimetics; pharmacophore; prevent; promoter; protein complex; protein degradation; public health relevance; screening; skills; small molecule; small molecule libraries; standard care; stereochemistry

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.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种侵袭性血癌，每年新发病例超过22，000例。目前的疗法是基于抑制蛋白酶体，一种多蛋白酶，执行多种基本的细胞活动。最重要的是，蛋白酶体负责降解错误折叠和/或无功能的蛋白质。蛋白酶体的抑制导致细胞死亡;因此，这种酶是癌症治疗的有效靶点。蛋白酶体抑制剂对MM特别有效，因为这种癌症已被证明表达异常高水平的这种蛋白质复合物。不幸的是，对先前开发的靶向负责蛋白质降解的蛋白酶体的催化部分的蛋白酶体抑制剂的抗性已经迅速发展，使得患者几乎没有替代治疗。需要一种新的治疗方法，仍然利用MM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不同亚基，即19 S调节颗粒（RP）。19 S RP负责识别和穿梭蛋白质以降解至蛋白酶体的催化核心。迄今为止，尚未开发出人19 S RP的小分子抑制剂。该培训奖学金的目的是通过合成限制性肽模拟物寡聚体（CPIO）的大型组合文库并应用测定方法确定我们的CPIO的结合能力和活性抑制来鉴定19 S RP抑制剂。CPIO文库将利用为肽和类肽开发的合成技术，但将掺入天然产物中发现的部分，因为这些化合物通常具有生物活性，并且通常比标准肽/类肽有效得多。我们将产生具有许多立体中心和骨架刚性的CPIO，这些特征以前没有被探索过。将使用结合测定法确定初始命中，以促进针对19 S RP快速筛选我们的大型文库。接下来，将测试与19 S RP结合的CPIO的酶活性抑制。最后，将最有效的CPIO抑制剂置于对蛋白酶体抑制剂具有抗性和敏感性的MM细胞系中，以测定其诱导细胞死亡的能力。我们预计，我们的新的小分子库将导致识别一种 19 S RP抑制剂，为MM提供了一种潜在的新治疗方法。