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（由申请人提供）：蛋白酶体是一种多催化蛋白水解酶，对于细胞内蛋白质的降解至关重要，从而调节信号转导、细胞周期控制、抗原加工和细胞凋亡等过程。蛋白酶体的抑制提供了一种有前景的方法。例如，肽硼酸硼替佐米 (bortezomib) 于 2003 年获得 FDA 批准用于治疗多发性骨髓瘤。然而，硼替佐米的作用给开发新型蛋白酶体抑制剂带来了新的挑战。文献中报道的大多数抑制剂与活性位点内的催化苏氨酸残基发生反应，然而，天然产物 TMC-95A 是一种大环肽。通过酶亚位点和大环延伸肽主链之间的氢键网络可逆地抑制蛋白酶体。该提案描述了新型大环的设计和合成策略。模拟含有TMC-95大环的羟吲哚的肽基抑制剂将被提出以这种设计为特征的共价结合和非共价结合抑制剂。在具体目标中，将研究1个非共价结合TMC-95类似物。在Specific Aim 2 中，将引入亲电陷阱来比较共价结合的TMC-95 类似物与非共价结合的类似物在Specific Aim 3 酶和细胞中。理化性质的测定和评估将确定所提出的抑制剂的生物学功效，这些化合物提供了一种有效抑制蛋白酶体的新的独特方法，可能导致新化疗药物的开发。

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