Developing chemoproteomic probes for studying protein chaperones in cancer

开发化学蛋白质组学探针来研究癌症中的蛋白质伴侣

• 批准号: 9401776
• 负责人: Adolfo Cuesta
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401776
• 关键词: Affinity; Alkynes; Amino Acids; Antineoplastic Agents; Apoptosis; Azides; Binding; Binding Sites; Biochemical; Biological Assay; Biotin; Cell Death; Cell Survival; Cells; Chemicals; Chemistry; Chronic Lymphocytic Leukemia; Client; Clinical; Clinical Trials; Complement; Complex; Copper; Crystallization; Cysteine; Data; Development; Dissociation; Drug Binding Site; Drug Targeting; Employee Strikes; Endoplasmic Reticulum; Fluorides; Genetic; HSP 90 inhibition; Heat-Shock Proteins 90; Human; Label; Lysine; Malignant Neoplasms; Measures; Methods; Mitochondria; Modification; Molecular; Molecular Chaperones; N-terminal; Normal Cell; Oncogenic; Organelles; Pharmaceutical Preparations; Phenotype; Prevalence; Protein Family; Protein Tyrosine Kinase; Proteins; Proteome; Purines; Reaction; Side; Solvents; Specificity; Structure; Surface; Testing; Time; Variant; alpha helix; base; biological systems; cancer cell; cancer therapy; chemical genetics; chemoproteomics; covalent bond; cycloaddition; cytotoxic; cytotoxicity; design; drug candidate; drug development; experimental study; fluorophore; in vivo; inhibitor/antagonist; interest; killings; new therapeutic target; novel strategies; paralogous gene; pre-clinical; residence; small molecule; targeted cancer therapy; thioether; tool

Project Summary / Abstract Targeted and rationally designed irreversible inhibitors are having a positive impact on the treatment of cancer. Ibrutinib is one of the first, rationally designed covalent inhibitors for the treatment of chronic lymphocytic leukemia. It covalently modifies a non-conserved cysteine residue in ATP-binding site of the tyrosine kinase, BTK. Occupancy probes that can assess inhibitor binding to BTK in vivo were essential tools in ibrutinib’s development. However, the use of this approach for other cancer-related targets is limited by cysteine’s scarcity in the proteome. The development of probes that target other nucleophiles is therefore necessary. The Hsp90 family of proteins is a potential target for the treatment of cancer, and there are currently seven Hsp90 inhibitors in clinical trials. Results from these trials have been modest at best. We propose to develop an occupancy probe of the Hsp90 family that covalently modifies a non-catalytic, surface-exposed lysine residue adjacent to the ATP binding site. We will use a structure-guided approach to make covalent inhibitors of the Hsp90 family that use an aryl sulfonyl fluoride as the electrophile. With these probes, we will dissect how inhibition of Hsp90 correlates to client degradation, Hsp70 induction, and cell death. Furthermore, we will explore the advantages of using a covalent inhibitor to treat cancer cells, and will specifically test whether complete, yet transient inhibition of Hsp90 is sufficient to kill cancer cells. Successful development of these probes will represent a significant advance for the scope of covalent probes. Furthermore, these will be the first ATP-binding site directed covalent inhibitors of the Hsp90 family.

项目摘要/摘要 靶向和合理设计的不可逆抑制剂正在对治疗产生积极影响 癌症的威胁。伊布鲁替尼是首批合理设计的治疗慢性阻塞性肺疾病的共价抑制剂之一。 淋巴细胞性白血病。它共价修饰ATP结合位点上的非保守半胱氨酸残基 酪氨酸激酶，BTK。能够评估体内与BTK结合的抑制剂的占位探针是必不可少的 Ibrutinib开发中的工具。然而，这种方法对其他癌症相关靶点的使用是有限的。 半胱氨酸在蛋白质组中的稀缺性。针对其他亲核分子的探针的发展是 因此，这是必要的。Hsp90蛋白家族是治疗癌症的潜在靶点，在那里 目前有七种Hsp90抑制剂正在进行临床试验。这些试验的结果充其量也是适中的。 我们建议开发一种Hsp90家族的占位探针，它可以共价修饰非催化， 与ATP结合位点相邻的表面暴露的赖氨酸残基。我们将使用结构指导的方法来 制造使用芳基磺酰氟作为电泳剂的Hsp90家族的共价抑制剂。有了这些 ，我们将剖析抑制Hsp90如何与客户降解、Hsp70诱导和细胞相关 死亡。此外，我们将探索使用共价抑制剂治疗癌细胞的优势，以及 将专门测试完全而短暂地抑制Hsp90是否足以杀死癌细胞。 这些探针的成功开发将标志着共价范围的重大进步 探测器。此外，这将是Hsp90家族的第一个ATP结合位点导向的共价抑制剂。