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: 7977240
• 负责人: GABRIELA CHIOSIS
• 金额: $ 25.44万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977240
• 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; Testing; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Toxic effect; Translations; Work; base; chronic autoimmune disease; cytokine; cytotoxicity; design; extracellular; feeding; follow-up; glucose-regulated proteins; in vivo; inhibitor/antagonist; member; numb protein; 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(申请人提供)：细胞质热休克蛋白90α和β(Hsp90？然后呢？)和内质网(ER)葡萄糖调节蛋白94(Grp94)是已知的主要哺乳动物Hsp90类似蛋白。每个都负责伴随一组不同的客户蛋白，并具有独特的生化作用，尽管在N-结构域和类似的调节配体结合腔中有50%的序列相同。而Hsp90？然后呢？Grp94在维持大量异常的恶性和神经退行性变驱动蛋白的功能构象方面发挥着重要作用，如激酶、转录因子和抗凋亡蛋白，但Grp94缺乏这些生化特征。相反，Grp94参与了有限数量的蛋白质的调节，这些蛋白质涉及免疫和炎症信号的传导。尤其重要的是Grp94在许多病理条件下调节免疫反应的新的治疗意义，在这些病理条件下，这种主要是内质网伴侣的蛋白转位到细胞表面和/或排泄到循环中。通过调节Toll样受体(TLRs)的细胞表面表达，Grp94与自身免疫性疾病、慢性炎症和脓毒症等病理过程有关。最近，Grp94与自身免疫性糖尿病的发病机制和血管并发症的发展之间的联系已经出现，这些并发症经常与疾病相关。此外，Grp94与促进类风湿性关节炎的慢性炎症有关。综上所述，这些发现表明Grp94是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，到目前为止，还没有报道具有治疗意义的选择性Grp94抑制剂支架，所有用于癌症临床评估的抑制剂对所有四个Hsp90成员都具有类似的亲和力。使用PAN-Hsp90抑制剂治疗免疫相关疾病，其中大多数需要长期给药，有明显的局限性，可能与不可接受的效益/毒性比有关。为了克服这些限制，本申请建议确定选择性和治疗相关的Grp94-小分子抑制剂支架。虽然由于Hsp90在配体结合口袋中具有高度的结构相似性而具有挑战性，但我们的初步数据证实，发现比Hsp90具有几个对数级选择性的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。它将采用一种迭代反馈策略，在该策略中，计算、合成和药物化学工作将提供给生化和生物信息，并从生化和生物信息中进行反馈。在这两年结束时，我们预计将获得重要的SAR信息，这些信息将教授主导Grp94抑制剂所必需的结构特征。我们的最终目标是为未来的临床翻译寻找线索。 公共卫生相关性：与密切相关的Paralog Hsp90不同，分子伴侣Grp94参与调节有限数量的蛋白质，涉及免疫和炎症信号的传导，表明致病Grp94的作用适合于选择性治疗调节。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都可以通过小分子抑制剂靶向Grp94来治疗。具有治疗适用性的Grp94伴侣的选择性小分子尚未报道，我们的应用首次描述了此类药物的发现和开发策略。