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（IL 18）是白细胞介素-1超家族成员，是炎性小体的重要效应分子 activation. IL 18信号传导通过其与IL 18受体（IL 18 R）α亚基的结合而起始，随后是IL 18受体（IL 18 R）α亚基的结合。 受体B亚基的募集以形成三元复合物。天然存在的IL 18拮抗剂，IL 18 结合蛋白（IL 18 BP），阻止IL 18与IL 18 R结合，通过抑制IL 18活性， 负反馈机制IL 18活性对于针对感染和肿瘤的免疫应答是重要的，但 它们也与一些炎症性疾病有关。因此，上调和下调IL-18活性都是有效的。 分别作为治疗癌症或炎性疾病的治疗方法。的 IL 18阻断治疗成人斯蒂尔病和自身炎性 噬血细胞综合征已由来自用人IL 18 BP的临床试验的初步结果证明。对 另一方面，最近发现IL 18 BP是抗肿瘤活性主要免疫屏障， IL 18和能够逃避IL 18 BP抑制的工程化的IL 18突变体显示出极大增强的抗- 小鼠模型中的肿瘤效应1.目前涉及IL 18调节的治疗方法 所有的活动都是基于蛋白质的。我们提案的最终目标是开发小分子， 上调或下调IL 18活性，其可用于癌症免疫疗法和治疗 炎症性疾病，分别。我们对IL 18的结构-功能研究做出了重要贡献 和IL 18 BP 2，3.我们揭示了IL 18表面上与IL 18 BP相互作用的三个口袋，并鉴定了小的 抑制IL-18活性或抑制IL-18 BP结合而对IL-18无有害作用的分子 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， 对于小分子治疗剂的结构导向设计至关重要。目标1.结构-功能研究 IL 18的小分子抑制剂。我们已经确定了一种在“热点”直接结合IL 18的小分子。 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。我们将开展更大规模的虚拟筛选、功能测定和 结构生物学，以确定其他化合物与不同的支架。目标2.结构-功能研究 IL 18 BP功能的小分子抑制剂。我们已经鉴定了两种直接结合IL 18的化合物 在不同的表面位置，阻断IL 18 BP结合，但保留IL 18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另外的化合物如IL 18 BP 抑制剂的用小分子调节IL 18信号传导是治疗糖尿病的一种新颖且有前途的方法。 炎症和癌症免疫疗法。成功地实现这些目标不仅会提供一个更好的 了解IL 18生物学，也为未来开发新疗法提供了关键平台 对抗一些人类疾病。