Developing small molecule inhibitors for modulating cytokine IL18 activities

开发调节细胞因子 IL18 活性的小分子抑制剂

• 批准号: 10226420
• 负责人: Junpeng Deng
• 金额: $ 24.05万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226420
• 关键词: Adult-Onset Still' s Disease; Anti-Inflammatory Agents; Autoimmune Diseases; Binding; Binding Proteins; Biochemical; Biological Assay; Biology; Clinical Trials; Complex; Crystallization; Crystallography; Development; Developmental Therapeutics Program; Disease; Engineering; Enhancers; Enzyme-Linked Immunosorbent Assay; Feedback; Foundations; Future; Goals; Hot Spot; Human; IL18 gene; Immune response; Immunotherapeutic agent; Immunotherapy; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Location; Malignant Neoplasms; Molecular; Mus; Pharmaceutical Preparations; Poxviridae; Property; Protein Inhibition; Proteins; Receptor Signaling; Research; Signal Transduction; Site; Structure; Surface; Surface Plasmon Resonance; Syndrome; Therapeutic; X-Ray Crystallography; antitumor effect; autoinflammatory; base; biophysical techniques; cancer immunotherapy; cytokine; design; human disease; inhibitor/antagonist; interleukin-18 binding protein; interleukin-18 receptor; member; mutant; novel; novel therapeutics; prevent; protein function; receptor; recruit; scaffold; screening; small molecule; small molecule inhibitor; small molecule therapeutics; structural biology; tumor; virtual; virtual screening

Interleukin 18 (IL18), a member of interleukin-1 superfamily, is a critical effector molecule of inflammasome activation. IL18 signaling is initiated by its binding to the IL18 receptor (IL18R) a subunit, followed by the recruitment of the receptor b subunit to form a ternary complex. A naturally occurring antagonist of IL18, IL18 binding protein (IL18BP), prevents IL18 from binding to IL18R, potently inhibiting IL18 activity through a negative feedback mechanism. IL18 activities are important for immune responses to infection and tumors, but they are also involved in some inflammatory diseases. Thus, both up- and down-modulating IL-18 activities are pursued as therapeutic approaches for treating cancers or inflammatory diseases, respectively. The therapeutic potential of IL18 blockage for the treatment of adult-onset Still’s disease and auto-inflammatory hemophagocytic syndrome has been demonstrated by initial results from clinical trials with human IL18BP. On the other hand, IL18BP was recently found to be a major immunotherapeutic barrier for anti-tumor activity of IL18, and an engineered IL18 mutant capable of evading IL18BP inhibition showed greatly enhanced anti- tumor effects in mouse models1. The current therapeutic approaches that involve the modulation of IL18 activities are all protein-based. The ultimate goal of our proposal is to develop small molecules that can either up- or down-modulate IL18 activities, which can be used in cancer immunotherapy and for treating inflammatory diseases, respectively. We have made significant contributions towards structure-function of IL18 and IL18BP2,3. We revealed three pockets on IL18 surface that interact with IL18BPs and identified small molecules that either inhibit IL-18 activities or inhibit IL18BP binding with no deleterious effect on IL18 activities. We propose following structure-function studies of the small-molecule IL-18 modulators, which are essential for structure-guided design of small-molecule therapeutics. Aim 1. Structure-function studies on small molecule inhibitors of IL18. We have identified a small molecule that directly binds IL18 at a ‘hot spot’ on the surface and inhibits its bioactivities. We will carry out further mechanistic studies on the compound by biochemical and biophysical approaches. We will carry out larger scale virtual screening, functional assays and structural biology to identify additional compounds with different scaffolds. Aim 2. Structure-function studies on small molecule inhibitors of IL18BP function. We have identified two compounds that directly bind IL18 at different surface locations, blocking IL18BP binding however retaining IL18 receptor signaling. We will use similar approaches as in aim 1 to characterize these compounds and further identify additional ones as IL18BP inhibitors. Modulating IL18 signaling with small molecules is a novel and promising approach for treatment of inflammation and cancer immunotherapy. Successfully accomplishing the aims will not only provide a better understanding of IL18 biology, but also provide critical platform for future development of new therapeutics against a number of human diseases.

白细胞介素 18 (IL18) 是白细胞介素 1 超家族的成员，是炎症小体的关键效应分子 激活。 IL18 信号传导是通过与 IL18 受体 (IL18R) 亚基的结合来启动的，然后 募集受体b亚基形成三元复合物。天然存在的 IL18 拮抗剂，IL18 结合蛋白 (IL18BP)，防止 IL18 与 IL18R 结合，通过 负反馈机制。 IL18 活性对于感染和肿瘤的免疫反应很重要，但是 它们还与一些炎症性疾病有关。因此，上调和下调 IL-18 活性均 分别作为治疗癌症或炎症性疾病的治疗方法。这 IL18 阻断治疗成人斯蒂尔病和自身炎症的治疗潜力 人类 IL18BP 临床试验的初步结果已证实噬血细胞综合征。在 另一方面，最近发现 IL18BP 是抗肿瘤活性的主要免疫治疗屏障。 IL18 和能够逃避 IL18BP 抑制的工程化 IL18 突变体显示出大大增强的抗- 小鼠模型中的肿瘤效应1。目前涉及 IL18 调节的治疗方法 活动均以蛋白质为基础。我们提案的最终目标是开发小分子，该小分子可以 上调或下调 IL18 活性，可用于癌症免疫治疗和治疗 分别是炎症性疾病。我们在 IL18 的结构-功能方面做出了重大贡献 和IL18BP2,3。我们揭示了 IL18 表面上与 IL18BP 相互作用的三个口袋，并鉴定了小的 抑制 IL-18 活性或抑制 IL18BP 结合且对 IL18 无有害影响的分子 活动。我们建议对小分子 IL-18 调节剂进行以下结构功能研究，它们是 对于小分子疗法的结构引导设计至关重要。目标 1. 结构-功能研究 IL18的小分子抑制剂。我们已经鉴定出一种小分子，可以直接在“热点”结合 IL18 表面并抑制其生物活性。我们将对该化合物进行进一步的机理研究 生物化学和生物物理方法。我们将进行更大规模的虚拟筛选、功能测定和 结构生物学来识别具有不同支架的其他化合物。目标 2. 结构功能研究 IL18BP 功能的小分子抑制剂。我们已经鉴定出两种直接结合 IL18 的化合物 在不同的表面位置，阻断 IL18BP 结合，但保留 IL18 受体信号传导。我们将使用 与目标 1 中类似的方法来表征这些化合物并进一步鉴定其他化合物如 IL18BP 抑制剂。用小分子调节 IL18 信号传导是一种新颖且有前途的治疗方法 炎症和癌症免疫治疗。成功实现目标不仅会提供更好的 了解 IL18 生物学，也为未来新疗法的开发提供重要平台 对抗多种人类疾病。