Characterization of A Novel Proteasome Inhibitor

新型蛋白酶体抑制剂的表征

• 批准号: 10597711
• 负责人: Jun O. Liu
• 金额: $ 52.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597711
• 关键词: Adverse effects; Animal Model; Antineoplastic Agents; Apoptotic; Archaea; Bacteria; Binding; Binding Sites; Biological Availability; Bortezomib; CRISPR screen; Cell Line; Cell physiology; Cells; Chemicals; Clinic; Complex; Cryoelectron Microscopy; Development; Disease; Drug Kinetics; Drug Targeting; Drug resistance; Eukaryota; Exhibits; Garbage; Genetic Transcription; Human; Hydrolysis; Immunoglobulins; Immunosuppressive Agents; Induction of Apoptosis; Lead; Libraries; Lymphoma; Malignant Neoplasms; Mediating; Mediator; Multiple Myeloma; Names; Normal Cell; Patients; Penetration; Peptide Hydrolases; Peptide Library; Periodicity; Peripheral Nervous System Diseases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Photoaffinity Labels; Plasma Cell Neoplasm; Play; Prodrugs; Property; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Regulation; Resistance; Resolution; Role; Route; Safety; Signal Transduction; Sirolimus; Site; Structure; Structure-Activity Relationship; Tacrolimus Binding Proteins; Therapeutic; Toxic effect; Work; analog; anti-cancer; cancer cell; cancer type; combinatorial; design; genome-wide; improved; in vivo; inhibitor; insight; multicatalytic endopeptidase complex; novel; novel anticancer drug; potential biomarker; predictive marker; prolyl oligopeptidase; proteostasis; refractory cancer; success; synergism; tool; tumor

The human proteasome plays an essential role in both protein homeostasis and in the regulation of multiple cellular processes from signal transduction to transcription. It has also become a proven target for developing drugs for treating multiple diseases including multiple myeloma and lymphoma. Several inhibitors of the proteasome, including bortezomib, carfilzomib and ixazomib, have been used in the clinic, responsible for prolonging lives of multiple myeloma patients. However, the existing proteasome-targeted drugs suffer from severe toxicity and rapid emergence of drug resistance, which also limits their potential in treating other types of diseases. We have developed a rapamycin-inspired macrocycle library known as rapafucins by fusing the FKBP-binding domain (FKBD) of rapamycin with a combinatorial peptide library. A screen of the rapafucin library in multiple myeloma cell line NCI-H929 led to the identification of a potent inhibitor, Rapaprotin that induces apoptosis in NCI-H929 cells. Rapaprotin exhibited selective toxicity to cancer cells over normal cells. It also has a unique mechanism of action, requiring activation by an intracellular protease through cleavage of the macrocycle into a linear form, Rapaprotin-L, which inhibits all three types of protease activities of the proteasome. Moreover, Rapaprotin is synergistic with bortezomib and is capable of resensitizing bortezomib-resistant cancer cells to the drug. In this application, we will investigate the mechanism of activation of Rapaprotin by the cellular protease, validating Rapaprotin-L as the active species for its cellular activity. We will obtain a high-resolution cryo-EM structure of the complex between proteasome and Rapaprotin-L. We will optimize the potency and pharmacokinetic property of Rapaprotin through design and synthesis of new analogs. The optimized analogs of Rapaprotin will be assessed for their efficacy in animal models of multiple myeloma and other diseases. The newly developed Rapaprotin analogs will serve as useful chemical probes to facilitate the study of the function and pharmacology of the proteasome and promising leads for developing a new class of anticancer and immunosuppressive drugs with lower adverse effects.

人类蛋白酶体在蛋白质稳态和 从信号转导到多种细胞过程的调节 转录。它也已成为开发治疗药物的经过验证的目标 多种疾病，包括多发性骨髓瘤和淋巴瘤。几种抑制剂 蛋白酶体，包括硼替佐米、卡非佐米和伊沙佐米，已被使用 在临床上，负责延长多发性骨髓瘤患者的生命。 然而，现有的蛋白酶体靶向药物存在严重的毒性和 耐药性的迅速出现，这也限制了它们的治疗潜力 其他类型的疾病。我们开发了雷帕霉素启发的大环化合物 通过融合 FKBP 结合域 (FKBD)，称为 rapafucins 文库 雷帕霉素与组合肽库。雷帕夫星文库的屏幕 多发性骨髓瘤细胞系 NCI-H929 导致了一种有效抑制剂的鉴定， Rapaprotin 可诱导 NCI-H929 细胞凋亡。雷帕蛋白展示 对癌细胞的选择性毒性高于对正常细胞的选择性毒性。它还具有独特的机制 的作用，需要通过细胞内蛋白酶的裂解来激活 大环化合物转化为线性形式 Rapaprotin-L，可抑制所有三种类型 蛋白酶体的蛋白酶活性。此外，Rapaprotin 与 硼替佐米，能够使硼替佐米耐药的癌细胞对硼替佐米重新敏感。 药品。在此应用中，我们将研究激活机制 通过细胞蛋白酶检测 Rapaprotin，验证 Rapaprotin-L 为活性物质 因为它的细胞活性。我们将获得高分辨率的冷冻电镜结构 蛋白酶体和 Rapaprotin-L 之间的复合物。我们将优化效力并 通过设计和合成新化合物来研究 Rapaprotin 的药代动力学特性 类似物。将评估 Rapaprotin 的优化类似物的功效 多发性骨髓瘤和其他疾病的动物模型。新开发的 雷帕蛋白类似物将作为有用的化学探针来促进以下研究 蛋白酶体的功能和药理学以及有希望的线索 开发一类新型抗癌和免疫抑制药物 不良影响。