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

项目总结 子宫内膜异位症是一种影响腹膜腔的炎症性疾病，已得到主要治疗。 内分泌调节剂通过抑制雌激素作用来限制生长。世界范围内， 有28种开发或上市的产品解决了子宫内膜异位症的内分泌轴问题。然而， 很少，如果有的话，药物发现努力将这种疾病的非荷尔蒙轴心作为独立治疗，或作为 间歇期内分泌抑制药的序贯治疗。深人共有的病理生理学 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、腹膜浅表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。这件事的重点是 拟议的研究是开发新型的、有效的、高选择性的Jun N末端激酶(JNK-I)抑制剂 可以阻断作为病变存活的病理基础的跨分化途径。 我们对苯达吡莫特(JNK-I)的初步结果已经验证了这种方法，证明了其等效性 在灵长类动物模型中，用GnRH拮抗剂可使AS病变消退。此外，结果是 啮齿动物、非人灵长类动物模型和人类模型(II期结果)显示病变消退 不影响在位子宫内膜或内源性激素水平。我们的项目将生殖 生物学家、免疫学家、药物化学家和生物医学工程师，在 学术和制药研究，以发现新的JNK-I并表征其对患者的潜力。 我们的计划融入了最先进的技术，以帮助实现我们的目标。在具体目标1中，我们 将优化c-jun氨基末端激酶(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。这些化合物的体外疗效将在建立后进行评估。 细胞系和原代人子宫内膜间质细胞。在具体目标2中，我们将比较 在药物发现中心制备的新型JNK-I在先前验证的小鼠中应用坦齐瑟替布 子宫内膜异位症模型与子宫内膜特异性ER？过度表达(ER？：OE)，启用 ER升高时抗炎治疗的评价？反应和黄体酮减退 敏感度。这些比较从来没有为JNK-I产生，并提供了一个机会来评估 基于JNK-I效力提高的治疗效果。在具体目标3中，我们将证明 月经组的新兴诊断方法可以根据患者的情况对患者进行分层，以便将来进行JNK-I治疗 月经流出液中巨噬细胞和NK细胞体外细胞因子的产生。这个 所有三个特定目标的目标产生了关于JNK-I在子宫内膜异位症中的作用的新信息 无论是已知的还是新颖的JNK-I。

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.