Discovery and development of potent inhibitors of Jun N-terminal kinase for non-hormonal treatment of endometriosis and associated pain

发现和开发 Jun N 末端激酶的有效抑制剂，用于子宫内膜异位症和相关疼痛的非激素治疗

• 批准号: 10669033
• 负责人: Stephen Sunderland Palmer
• 金额: $ 57.66万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669033
• 关键词: Address; Adoption; Affect; Affinity; Agonist; Animal Model; Anti-Inflammatory Agents; Aromatase; Autologous; Biological Markers; Biomedical Engineering; Cells; Chemistry; Clinical; Clinical Research; Companions; Contraceptive Agents; DNA; Development; Diagnostic; Disease; Disease Management; Endocrine; Endometrial; Endometrial Stromal Cell; Endometriomas; Endometrium; Enzymes; Epithelium; Equilibrium; Estrogen Antagonists; Estrogens; Evaluation; Fibroblasts; Foundations; Functional disorder; Funding; Future; Gonadotropin Hormone Releasing Hormone; Greater sac of peritoneum; Growth; Gynecologic; Health; Hormonal; Hormone Antagonists; Hormones; Human; Immune; Immunologist; Immunosuppression; In Vitro; Infertility; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Interruption; Leadership; Lesion; Libraries; MAPK8 gene; Macrophage; Marketing; Mediating; Medicine; Medroxyprogesterone 17-Acetate; Mesenchymal; Metabolic; Modeling; Mus; N-terminal; National Institute of Child Health and Human Development; Natural Killer Cells; Oral; Pain; Pain Threshold; Pain management; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Peritoneal; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Pre-Clinical Model; Primates; Production; Productivity; Progesterone; Progesterone Receptors; Reporting; Research; Resistance; Rodent; Role; Sequential Treatment; Stratification; Surveys; Syndrome; Technology; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; United States; Uterus; Woman; Women' s Health; analog; antagonist; biomarker panel; college; comparative efficacy; cytokine; diagnostic technologies; drug development; drug discovery; endometriosis; established cell line; eutopic endometrium; experience; genotoxicity; hypothalamic pituitary ovarian axis; immune function; immunological status; improved; inhibitor; interest; kinase inhibitor; mouse model; nonhuman primate; novel; novel therapeutics; overexpression; pain perception; pain symptom; patient population; patient stratification; pre-clinical; preclinical study; programs; public health relevance; reproductive; responders and non-responders; response; side effect; targeted treatment; technology platform; transdifferentiation

PROJECT SUMMARY Endometriosis is an inflammatory disease affecting the peritoneal cavity that has been treated predominantly with endocrine modulators to impose growth restriction through suppression of estrogen action. Worldwide, there are 28 development or marketed products that address the endocrine axis of endometriosis. However, few, if any drug discovery efforts address the non-hormonal axes of this disease as stand-alone therapy, or as sequential therapy during hiatus from endocrine-suppressing agents. The pathophysiology shared by deep infiltrating endometriosis, superficial peritoneal endometriosis and ovarian endometrioma includes epithelial- mesenchymal trans-differentiation (EMT) and fibroblast-myofibrobocyte trans-differentiation. The focus of this proposed research is to develop novel, potent, highly selective inhibitors of Jun N-terminal kinase (JNK-I) that can interrupt trans-differentiation pathways that are the pathological basis for lesion survival. Our preliminary results with bentamipimod (JNK-I) have validated this approach demonstrating equivalent regression of lesions as were obtained with GnRH antagonist in primate models. Furthermore, results in rodent, non-human primate models, and in humans (Phase II results) demonstrate regression of lesions without impact on eutopic endometrium, or endogenous hormone levels. Our project integrates reproductive biologists, immunologists, medicinal chemists and biomedical engineers with demonstrated leadership in academic and pharmaceutical research to discover novel JNK-I and characterize their potential for patients. Our program incorporates state-of-the-art technologies to help achieve our objectives. In Specific Aim 1, we will optimize affinity and permeability of c-jun N-terminal kinase (JNK-I) obtained following two rounds of selection from our DNA-encoded Chemistry Technology (DEC-Tec) libraries at Baylor College of Medicine containing over 4 billion compounds. The efficacy of these compounds in vitro will be evaluated in established cell lines and in primary human endometrial stromal cells. In Specific Aim 2, we will compare the efficacy of novel JNK-I prepared at the Center for Drug Discovery to tanzisertib in a previously validated mouse model of endometriosis with endometrium-specific ER? overexpression (ER?:OE) that enables evaluation of anti-inflammatory therapies amidst elevated ER? response and compromised progesterone sensitivity. These comparisons have never been generated for JNK-I and provide an opportunity to assess treatment efficacy based on improved potency of JNK-I. In Specific Aim 3, we will demonstrate that emerging diagnostics of the menstrualome can stratify patients for future JNK-I therapy based on their ex vivo cytokine production from macrophages and NK cells obtained from menstrual effluent. The objectives for all three Specific Aims generate new information regarding the action of JNK-I in endometriosis for both known and novel JNK-I.

项目概要 子宫内膜异位症是一种影响腹膜腔的炎症性疾病，目前主要治疗 与内分泌调节剂一起通过抑制雌激素作用来限制生长。全世界， 有 28 种正在开发或上市的产品可解决子宫内膜异位症的内分泌轴问题。然而， 很少有药物发现工作将这种疾病的非激素轴作为独立疗法或作为 内分泌抑制剂中断期间的序贯治疗。深部共有的病理生理学 浸润性子宫内膜异位症、浅表性腹膜子宫内膜异位症和卵巢子宫内膜异位症包括上皮性子宫内膜异位症和卵巢子宫内膜异位症。 间充质转分化（EMT）和成纤维细胞-肌纤维细胞转分化。本次的重点 拟议的研究是开发新型、有效、高选择性的 Jun N 末端激酶 (JNK-I) 抑制剂 可以中断转分化途径，而转分化途径是病变存活的病理基础。 我们对苯他莫德 (JNK-I) 的初步结果验证了这种方法，证明了其等效性 在灵长类动物模型中使用 GnRH 拮抗剂获得的损伤消退。此外，结果是 啮齿动物、非人类灵长类动物模型和人类（第二阶段结果）显示病变消退 对在位子宫内膜或内源性激素水平没有影响。我们的项目整合了生殖 生物学家、免疫学家、药物化学家和生物医学工程师，在 学术和药物研究发现新型 JNK-I 并表征其对患者的潜力。 我们的计划采用了最先进的技术来帮助实现我们的目标。在具体目标 1 中，我们 将优化两轮后获得的 c-jun N 末端激酶 (JNK-I) 的亲和力和通透性 从贝勒医学院的 DNA 编码化学技术 (DEC-Tec) 库中选择 含有超过 40 亿种化合物。这些化合物的体外功效将在已建立的条件下进行评估 细胞系和原代人子宫内膜基质细胞。在具体目标 2 中，我们将比较以下方法的功效： 药物发现中心制备的新型 JNK-I 在先前验证的小鼠中用于 tanzisertib 子宫内膜异位症模型与子宫内膜特异性ER？过度表达 (ER?:OE) 使 ER 升高时抗炎治疗的评估？反应和黄体酮受损 敏感性。这些比较从未针对 JNK-I 进行过，并提供了评估的机会 治疗效果基于 JNK-I 效力的提高。在具体目标 3 中，我们将证明 新兴的月经组诊断可以根据患者的情况对未来的 JNK-I 治疗进行分层 从月经排出物中获得的巨噬细胞和 NK 细胞离体产生细胞因子。这 所有三个具体目标的目标产生了有关 JNK-I 在子宫内膜异位症中的作用的新信息 对于已知的和新颖的 JNK-I。