TMC-95 derived peptide macrocycles as inhibitors of the proteasome

TMC-95 衍生肽大环化合物作为蛋白酶体抑制剂

• 批准号: 8956686
• 负责人: Marion Gabriele Gotz
• 金额: $ 26.06万
• 依托单位: WHITMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956686
• 关键词: Active Sites; Adverse effects; Affect; Aldehydes; Amino Acids; Apoptosis; Beryllium; Binding; Biological; Biological Assay; Biological Factors; Boronic Acids; Bortezomib; Cell Cycle Regulation; Cellular Assay; Complex; Development; Elements; Enzyme Kinetics; Enzymes; Ethers; Evaluation; Exhibits; FDA approved; Goals; Hydrogen Bonding; Lead; Literature; Malignant Neoplasms; Metabolism; Modification; Molecular Conformation; Multiple Myeloma; N-terminal; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Plasma; Plasma Cells; Process; Property; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Reporting; Series; Signal Transduction; Solubility; Structure; System; TMC-95A; Threonine; Vertebral column; Work; analog; antigen processing; cancer cell; cancer therapy; chemotherapeutic agent; design; divinyl sulfone; experience; improved; inhibitor/antagonist; interest; large scale production; multicatalytic endopeptidase complex; neoplastic; novel; novel strategies; oxindole; phenyl ether; public health relevance; success; therapeutic target

 DESCRIPTION (provided by applicant): The proteasome is a multicatalytic proteolytic enzyme that is essential for the degradation of intracellular proteins thereby regulating processes such as signal-transduction, cell-cycle control, antigen processing and apoptosis. Inhibition of the proteasome offers a promising approach in the treatment of cancer. The peptide boronic acid bortezomib, for example, was FDA-approved for the treatment of multiple myeloma in 2003. Recently emerging side effects of bortezomib, however, have renewed the challenge to develop novel proteasome inhibitors. The majority of the inhibitors reported in the literature react with te catalytic threonine residue within the active site. The natural product TMC-95A, however, is a macrocyclic peptide that reversibly inhibits the proteasome through a hydrogen-bonding network between the enzyme subsites and the extended peptide backbone of the macrocycle. This proposal describes the design and synthetic strategy of novel macrocyclic peptidyl inhibitors that mimic the oxindole containing TMC-95 macrocycle. Both covalently and non-covalently binding inhibitors featuring this design are proposed. Three specific aims will explore these modifications. In Specific Aim 1 non-covalently binding TMC-95 analogs will be investigated. In Specific Aim 2 an electrophilic trap will be incorporated to compare covalently binding TMC-95 analogs to non-covalently binding analogs. In Specific Aim 3 enzyme and cellular assays and evaluation of physicochemical properties will determine the biological efficacy of the proposed inhibitors. These compounds offer a new and unique approach to effectively inhibit the proteasome, potentially leading to the development of new chemotherapeutic agents.

 描述（由应用程序提供）：蛋白酶体是一种多催化蛋白水解酶，对于降解细胞内蛋白是必不可少的，从而调节了信号转移，细胞周期控制，抗原处理和凋亡的过程。蛋白酶体的抑制作用为癌症治疗提供了有希望的方法。例如，pepperonib bortezomib在2003年被FDA批准用于治疗多发性骨髓瘤。然而，最近硼替佐米的新兴副作用已重新引起了开发新型蛋白酶体抑制剂的挑战。文献中报告的大多数抑制剂与活性部位内的催化苏氨酸保留反应。然而，天然产物TMC-95A是一种大环肽，可逆地通过酶亚矿物与大环的扩展肽主链之间的氢键网络可逆地抑制蛋白酶体。该提案描述了模仿含有TMC-95大环的氧丝的新型大环petidyl抑制剂的设计和合成策略。提出了具有此设计的共价和非共价结合抑制剂。三个具体目标将探索这些修改。在特定目标中，将研究非共价结合的TMC-95类似物。在特定的目标2中，将掺入一个亲电陷阱，以将共价结合的TMC-95类似物与非共价结合类似物进行比较。在特定目标中，3酶和细胞测定以及对物理特性的评估将决定所提出的抑制剂的生物学有效性。这些化合物提供了一种新的独特方法来有效抑制蛋白酶体，并有可能导致新的化学治疗剂的发展。

项目成果

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome.

• DOI: 10.1021/acsmedchemlett.5b00401
• 发表时间: 2016-01
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: David L. Wilson;Isabel Meininger;Z. Strater;S. Steiner;Frederick M. Tomlin;Julia Z Z Wu-Julia-Z-Z-Wu-2146667014;Haya Jamali;D. Krappmann;M. Götz

Macrocyclic Oxindole Peptide Epoxyketones-A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome.

大环羟吲哚肽环氧酮 - 20S 蛋白酶体大环抑制剂的比较研究。

• DOI: 10.1021/acsmedchemlett.4c00017
• 发表时间: 2024
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Götz,MarionG;Godwin,Kacey;Price,Rachel;Dorn,Robert;Merrill-Steskal,Gabriel;Klemmer,William;Hansen,Hunter;Produturi,Gautam;Rocha,Megan;Palmer,Mathias;Molacek,Lea;Strater,Zack;Groll,Michael
• 通讯作者: Groll,Michael