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; 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.

人蛋白酶体在蛋白质稳态和 从信号转导到的多个细胞过程调节 转录。它也已成为开发用于治疗药物的目标 多种疾病，包括多种骨髓瘤和淋巴瘤。几种抑制剂 蛋白酶体，包括bortezomib，carfilzomib和ixazomib，已被使用 在诊所中，负责延长多个骨髓瘤患者的寿命。 但是，现有的靶向蛋白酶体的药物患有严重的毒性和 耐药性的快速出现，这也限制了其治疗的潜力 其他类型的疾病。我们已经开发了雷帕霉素风格的大环 通过融合FKBP结合域（FKBD）的图书馆称为Rapafucins 带有组合肽库的雷帕霉素。 Rapafucin库的屏幕 多发性骨髓瘤细胞系NCI-H929导致鉴定有效的抑制剂， Rapaprotin诱导NCI-H929细胞凋亡。 Rapaprotin展示 在正常细胞上对癌细胞的选择性毒性。它也有独特的机制 作用，需要通过裂解细胞内蛋白酶激活 大环成形式，即rapaprotin-l，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，能够使硼替佐米抗性癌细胞的敏感性 药品。在此应用中，我们将研究激活的机理 细胞蛋白酶的Rapaprotin，将Rapaprotin-L验证为活性物种 其细胞活性。我们将获得高分辨率的低分辨率冷冻结构 蛋白酶体和Rapyaprotin-L之间的复杂。我们将优化效力和 RAPROTIN的药代动力学特性通过设计和合成 类似物。将对Rapaprotin的优化类似物评估其功效 多发性骨髓瘤和其他疾病的动物模型。新开发 Rapaprotin类似物将作为有用的化学探针，以促进研究 蛋白酶体和有前途的铅的功能和药理学 开发一种新的抗癌和免疫抑制药物， 不利影响。