Small molecule GPR10 antagonists for the treatment of uterine fibroids

项目摘要/摘要 子宫肌瘤(UL，子宫肌瘤)是一种良性的子宫平滑肌细胞肿瘤。 子宫肌层。子宫肌瘤是子宫切除术最常见的临床指征，通常 过早地终止女性的生育能力。在2010年，每年估计子宫肌瘤的费用 美国的债务总额高达344亿美元。然而，尽管如此，目前还没有批准的药物可以 为UL提供有效的长期治疗。还有一个尚未得到满足的需求，即识别分子靶标和 开发治疗子宫肌瘤的疗法。我们研究的目标是了解分子 探讨子宫UL的发病机制，以期开发有效的药物治疗方法。调节异常的PI3K/AKT 导致mTOR激活的途径在肌瘤的发病机制中起着重要作用。我们的 初步数据表明，GPR10，一种通常由肿瘤抑制因子在外周沉默的GPCR REST/NRSF，几乎是普遍过度表达的人类肌瘤，它含有非常高程度的 其他标记的异质性。此外，肌瘤中的REST蛋白显著减少。对美国经济至关重要 目前的研究项目是，GPR10的激活或REST的丢失会触发PI3K/AKT信号转导和肿瘤细胞 扩散。我们假设REST的丢失导致了GPR10在肌瘤中的表达，而这 基因表达异常促进细胞增殖参与子宫内膜异位症的发病 肌瘤。本项目将确定REST-GPR10-AKT-mTOR途径在 用体外方法和新的体内遗传模型研究子宫肌瘤的发病机制。此外， 该项目将识别、进行结构活性关系(SAR)研究，并进行临床前测试，小分子 GPR10拮抗剂作为UL的潜在治疗药物。

PROJECT SUMMARY/ABSTRACT Uterine fibroids (UL, uterine leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. Leiomyomas represent the most frequent clinical indication for hysterectomy that often prematurely ends a woman's fertility. In the year 2010, the estimated annual cost of uterine fibroid tumors in the United States was up to $34.4 billion. Yet in spite of this, there are currently no approved drugs that can provide effective, long-term treatment for UL. There is an unmet need to identify molecular targets and to develop therapies to treat uterine fibroids. The goal of our research is to understand the molecular pathogenesis of uterine UL so that effective pharmacotherapies could be developed. Dysregulated PI3K/AKT pathway leading to the activation of mTOR play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas, which harbor a very high degree of heterogeneity in other markers. Further, REST protein is dramatically reduced in leiomyomas. Crucial to the current project, the activation of GPR10, or the loss of REST triggers PI3K/AKT signaling and tumor cell proliferation. We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that REST-GPR10-AKT-mTOR pathway has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models. Additionally, the project will identify, conduct structure activity relationship (SAR) studies, and pre-clinically test, small molecule GPR10 antagonists as potential treatments for UL.