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.

白介素18（IL18）是白介素-1超家族的成员，是炎性体的关键效应分子 激活。 IL18信号是通过其与IL18受体（IL18R）的亚基结合而引发的，然后是 接收器B亚基的募集以形成三元络合物。 IL18，IL18的天然拮抗剂 结合蛋白（IL18BP）可防止IL18与IL18R结合，可能通过A抑制IL18活性 负反馈机制。 IL18活动对于免疫调查和肿瘤的免疫调查很重要，但是 他们还参与了一些炎症性疾病。那是向上调教的IL-18活动是 作为治疗癌症或炎症性疾病的治疗方法。 IL18阻塞的治疗潜力用于治疗成人静止病和自动炎症 人类IL18BP的临床试验的初步结果证明了造血细胞综合征。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和一种能够逃避IL18BP抑制的工程IL18突变体显示出非常增强的抗抗 小鼠模型中的肿瘤效应1。当前涉及调节IL18的治疗方法 活动都是基于蛋白质的。我们建议的最终目标是开发可以 上或下调的IL18活动，可用于癌症免疫疗法并治疗 分别炎症性疾病。我们为IL18的结构功能做出了重大贡献 和IL18BP2,3。我们揭示了与IL18bps相互作用的IL18表面上的三个口袋 抑制IL-18活性或抑制IL18BP结合而没有有害影响IL18的分子 活动。我们提出了小分子IL-18调节剂的以下结构功能研究，这是 对于小分子疗法的结构引导设计所必需的。目标1。关于结构功能研究 IL18的小分子抑制剂。我们已经确定了一个直接在“热点”上直接结合IL18的小分子 表面并抑制其生物活性。我们将通过 生化和生物物理方法。我们将进行更大的虚拟筛选，功能测定和 结构生物学，以鉴定具有不同脚手架的其他化合物。目标2。结构功能研究 在IL18bp功能的小分子抑制剂上。我们已经确定了两种直接结合IL18的化合物 在不同的表面位置，阻止IL18BP结合，但是保持IL18受体信号传导。我们将使用 类似的方法与AIM 1中的表征表征这些化合物并进一步识别为IL18BP 抑制剂。用小分子调节IL18信号传导是一种新颖而有希望的治疗方法 炎症和癌症免疫疗法。成功完成目标不仅可以提供更好的 了解IL18生物学，但也为未来开发新疗法提供了关键的平台 反对许多人类疾病。