Design, synthesis and evaluation of selective Grp94 inhibitors

选择性 Grp94 抑制剂的设计、合成和评价

• 批准号: 8065965
• 负责人: GABRIELA CHIOSIS
• 金额: $ 20.6万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065965
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Affinity; Apoptotic; Autoimmune Diabetes; Autoimmune Diseases; Automobile Driving; Back; Behavior; Binding; Biochemical; Biological; Biological Assay; Blood Circulation; Blood Vessels; Cell Line; Cell membrane; Cell surface; Cells; Cellular Assay; Chronic; Client; Clinical; Coronary Thrombosis; Cytotoxic agent; Data; Development; Diabetes Mellitus; Disease; Educational process of instructing; Elements; Endoplasmic Reticulum; Evaluation; Fingerprint; Fluorescence Polarization; Frequencies; Future; Glucose; Goals; Grant; Heat-Shock Proteins 90; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Laboratories; Lead; Ligand Binding; Link; Lipopolysaccharides; Malignant Neoplasms; Measures; Molecular Chaperones; Molecular Conformation; N Domain; Nerve Degeneration; Pathogenesis; Pathologic Processes; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Production; Proteins; Purines; Reading; Regulation; Reporting; Rheumatoid Arthritis; Role; Screening procedure; Sepsis; Septic Shock; Signal Transduction; Stroke; Structure; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Toxic effect; Translations; Work; base; chronic autoimmune disease; computational chemistry; cytokine; cytotoxicity; design; extracellular; feeding; follow-up; glucose-regulated proteins; in vivo; inhibitor/antagonist; member; paralogous gene; public health relevance; purine; research clinical testing; scaffold; small molecule; transcription factor

DESCRIPTION (provided by applicant): Cytoplasmic heat shock protein 90 alpha and beta (Hsp90? and ?) and endoplasmic reticulum (ER) glucose-regulated protein94 (Grp94) are the main known mammalian Hsp90 paralogs. Each is responsible for chaperoning a distinct set of client proteins and has a unique biochemical role, despite 50% sequence identity in N-domains and analogous regulatory ligand binding cavities. While Hsp90? and ? have important roles in maintaining the functional conformation of a large number of aberrant malignancy- and neurodegeneration- driving proteins, such as kinases, transcription factors and anti-apoptotic proteins, Grp94 lacks these biochemical hallmarks. In contrast, Grp94 is involved in the regulation of a restricted number of proteins involved in channeling immune and inflammatory signals. Of especial importance are emerging therapeutic implications of Grp94 in regulating the immune response in many pathological conditions, in which this mainly ER chaperone, translocates to the cell surface and/or is excreted into the circulation. Through regulation of cell surface expression of Toll-like receptors (TLRs), Grp94 is associated with pathological processes like autoimmune disease, chronic inflammatory conditions and sepsis. Recently, a link between Grp94 and the pathogenesis of autoimmune diabetes and the development of vascular complications, frequently associated with the disease, has emerged. Furthermore, Grp94 is implicated in promoting chronic inflammation in rheumatoid arthritis. Taken together, these findings suggest Grp94 as a valid target for therapeutic intervention, and position the Grp94 inhibitors as potential therapeutics in the treatment of immune-related disorders. To date however, no selective Grp94 inhibitor scaffold of therapeutic significance has been reported, and all inhibitors in clinical evaluation for cancers act with similar affinity on all four Hsp90 members. The use of pan-Hsp90 inhibitors for immune-related disorders, of which most require chronic administration, has its obvious limitations, and may be associated with unacceptable benefit to toxicity ratio. To overcome these limitations, this application proposes to identify selective and therapeutically relevant Grp94-small molecule inhibitor scaffolds. While challenging because of the high structural similarity among Hsp90s in the ligand binding pocket, our preliminary data confirm that discovery of Grp94 inhibitors with several log-orders of selectivity over Hsp90s is possible. Our proposal offers a pioneering perspective on the discovery, design, synthesis and evaluation of selective Grp94 inhibitors. It will employ an iterative feed-back strategy in which computational, synthetic and medicinal chemistry efforts feed into and from biochemical and biological information. At the end of the two years we anticipate to have gained important SAR information that will teach on the structural features imperative for a lead Grp94 inhibitor. Our ultimate goal is to identify leads for future clinical translation. PUBLIC HEALTH RELEVANCE: The molecular chaperone Grp94, unlike is closely related paralog Hsp90, is involved in the regulation of a restricted number of proteins involved in channeling immune and inflammatory signals, indicating that the pathogenic Grp94 roles are amenable for selective therapeutic modulation. As such, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis and stroke can be potentially treated by targeting Grp94 with small molecule inhibitors. Selective small molecules of the Grp94 chaperone with therapeutic applicability are yet to be reported, and our application is first to describe strategies for the discovery and development of such agents.

描述（由申请人提供）：细胞质热休克蛋白90α和β（Hsp90α和β）和内质网（ER）葡萄糖调节蛋白94（Grp94）是主要已知的哺乳动物Hsp90旁系同源物。尽管 N 结构域和类似的调节配体结合腔具有 50% 的序列同一性，但每一个都负责陪伴一组不同的客户蛋白，并具有独特的生化作用。而Hsp90？和 ？ Grp94 在维持大量异常恶性肿瘤和神经变性驱动蛋白（例如激酶、转录因子和抗凋亡蛋白）的功能构象方面发挥着重要作用，但 Grp94 缺乏这些生化特征。相比之下，Grp94 参与调节有限数量的蛋白质，这些蛋白质参与通道免疫和炎症信号。特别重要的是 Grp94 在调节许多病理状况下的免疫反应方面的新兴治疗意义，其中这种主要是 ER 伴侣，易位到细胞表面和/或排泄到循环中。通过调节 Toll 样受体 (TLR) 的细胞表面表达，Grp94 与自身免疫性疾病、慢性炎症和败血症等病理过程相关。最近，Grp94 与自身免疫性糖尿病的发病机制以及经常与该疾病相关的血管并发症的发展之间的联系已经出现。此外，Grp94 还与促进类风湿性关节炎的慢性炎症有关。总而言之，这些发现表明 Grp94 作为治疗干预的有效靶点，并将 Grp94 抑制剂定位为治疗免疫相关疾病的潜在疗法。然而，迄今为止，尚未报道具有治疗意义的选择性 Grp94 抑制剂支架，并且癌症临床评估中的所有抑制剂对所有四个 Hsp90 成员均具有相似的亲和力。使用泛Hsp90抑制剂治疗大多数需要长期给药的免疫相关疾病有其明显的局限性，并且可能与不可接受的获益/毒性比有关。为了克服这些限制，本申请提出鉴定选择性和治疗相关的 Grp94-小分子抑制剂支架。虽然由于配体结合口袋中 Hsp90 之间的高度结构相似性而具有挑战性，但我们的初步数据证实，发现具有比 Hsp90 多个对数级选择性的 Grp94 抑制剂是可能的。我们的提案为选择性 Grp94 抑制剂的发现、设计、合成和评估提供了开创性的视角。它将采用迭代反馈策略，将计算、合成和药物化学工作纳入生化和生物信息。两年结束时，我们预计将获得重要的 SAR 信息，这些信息将教授先导 Grp94 抑制剂所需的结构特征。我们的最终目标是确定未来临床转化的线索。 公共健康相关性：与密切相关的旁系同源物 Hsp90 不同，分子伴侣 Grp94 参与调节有限数量的蛋白质，这些蛋白质参与通道免疫和炎症信号，表明 Grp94 的致病作用适合选择性治疗调节。因此，感染性休克、自身免疫性疾病、慢性炎症、糖尿病、冠状动脉血栓形成和中风可以通过用小分子抑制剂靶向 Grp94 来治疗。具有治疗适用性的 Grp94 伴侣的选择性小分子尚未有报道，我们的应用首先描述了此类药物的发现和开发策略。