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

基本信息

  • 批准号:
    10669033
  • 负责人:
  • 金额:
    $ 57.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目摘要 子宫内膜异位症是一种炎症性疾病,影响腹膜腔,已被主要治疗 与内分泌调节剂一起通过抑制雌激素作用来施加生长限制。在世界范围内, 有28种开发或上市的产品涉及子宫内膜异位症的内分泌轴。然而,在这方面, 很少,如果有的话,药物发现努力解决这种疾病的非激素轴作为独立的治疗,或作为 内分泌抑制剂中断期间的序贯治疗。深呼吸所共有的病理生理学 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腺瘤包括上皮性- 间充质转分化(EMT)和成纤维细胞-肌纤维细胞转分化。的重点 建议的研究是开发新的、有效的、高选择性的Jun N-末端激酶(JNK-I)抑制剂, 可以中断作为损伤存活的病理基础的转分化途径。 我们对阿阿米莫德(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用GnRH拮抗剂获得的病变消退。此外,结果 啮齿类动物、非人灵长类动物模型和人类(II期结果)显示病变消退 而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,在以下方面具有领导地位: 学术和药学研究,以发现新的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, 将优化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实验室中进行评估。 细胞系和原代人子宫内膜间质细胞中。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用于先前验证的小鼠中的tanzisertib 子宫内膜特异性ER的子宫内膜异位症模型?过表达(ER?:OE),使 在ER升高的情况下评价抗炎治疗?反应和受损的孕酮 灵敏度JNK-I从未进行过这些比较,因此有机会评估 基于JNK-I的改善的效力的治疗功效。在具体目标3中,我们将证明, 新出现的JNK-I基因组诊断可以根据患者的临床表现对患者进行分层,以用于将来的JNK-I治疗。 从月经流出物获得的巨噬细胞和NK细胞的离体细胞因子产生。的 所有三个特定目的的目的产生了关于JNK-I在子宫内膜异位症中作用的新信息 对于已知的和新的JNK-I。

项目成果

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Stephen Sunderland Palmer其他文献

Stephen Sunderland Palmer的其他文献

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{{ truncateString('Stephen Sunderland Palmer', 18)}}的其他基金

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:
    10467991
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:

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