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: 10393624
• 负责人: Junpeng Deng
• 金额: $ 18.97万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393624
• 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; antagonist; antitumor effect; autoinflammatory; base; biophysical techniques; cancer immunotherapy; cytokine; design; human disease; inhibitor; interleukin-18 binding protein; interleukin-18 receptor; member; mutant; novel; novel therapeutics; prevent; protein function; rational design; receptor; recruit; scaffold; screening; small molecule; small molecule inhibitor; small molecule therapeutics; structural biology; translational potential; 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，是炎症小体的关键效应分子 激活。IL18信号是由其与IL18受体(IL18R)的一个亚单位结合而启动的，随后是 募集受体b亚单位以形成三元复合体。天然产生的IL18拮抗剂IL18 结合蛋白(IL18BP)，阻止IL18与IL18R结合，通过一种 负反馈机制。IL18活性对感染和肿瘤的免疫反应很重要，但 他们还与一些炎症性疾病有关。因此，上调和下调IL-18活性都是 分别作为治疗癌症或炎症性疾病的治疗方法。这个 白介素18阻断治疗成人斯蒂尔病和自体炎症的可能性 噬血细胞综合征已被人类IL18BP临床试验的初步结果所证实。在……上面 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和可逃避IL18BP抑制的工程化IL18突变体表现出显著的抗 肿瘤对小鼠模型的影响1。目前涉及IL-18调节的治疗方法 活动都是以蛋白质为基础的。我们提议的最终目标是开发出能够 上调或下调IL18活性，可用于癌症免疫治疗和治疗 炎症性疾病。我们对IL18的结构和功能做出了重大贡献 和IL18BP2，3。我们发现IL18表面有三个与IL18BPs相互作用的口袋，并发现了小的 抑制IL-18活性或抑制IL18BP结合而对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 对小分子疗法的结构导向设计至关重要。目的：1.青蒿素的结构功能研究 IL18的小分子抑制剂。我们已经确定了一种小分子，它直接与IL18在“热点”结合 并抑制其生物活性。我们将通过以下方式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查、功能检测和 结构生物学，用于鉴定具有不同支架的其他化合物。目标2.结构-功能研究 关于IL18BP功能的小分子抑制剂。我们已经确定了两种直接与IL18结合的化合物 在不同的表面位置，阻断IL18BP结合，但保留IL18受体信号。我们将使用 与目标1类似的方法来表征这些化合物，并进一步确定其他化合物为IL18BP 抑制剂。用小分子调节IL18信号是一种新的、有前途的治疗方法 炎症和癌症免疫治疗。成功实现这些目标不仅将提供更好的 对IL18生物学的了解，也为未来新疗法的发展提供了关键平台 对抗多种人类疾病。