Reposition and Optimization of Deferiprone for Breast Cancer Therapy

项目摘要/摘要：2020年，估计将有约276，480例浸润性乳腺癌新发病例 (BCa)在美国的妇女中，估计造成约42，170人死亡。两种常见的机制 BCa的维持是表观遗传功能障碍和雌激素等内分泌蛋白的功能障碍 受体（ER）。本申请中提出的研究的具体焦点是重新利用去铁酮（Def）， FDA批准的铁螯合剂，作为发现新型组蛋白赖氨酸脱甲基酶（KDM）的模板 针对BCa治疗优化的抑制剂。大多数已经或正在临床开发的化合物表现出 对BCa亚型有更好的疗效。在这方面，利用ER信号传导的治疗干预措施 故障，超过70%的BCAs的驱动因素，在BCa治疗和/或化疗中取得了一定的成功， 预防然而，尽管最初的好处，大多数患者最终复发，由于获得性耐药性，这些 毒品此外，三阴性乳腺癌（TNBC）没有靶向治疗选择，BCa 缺乏ER、人表皮生长因子受体2（HER 2）和孕酮受体（PR）的亚型， 占BCa发病率的20%以上。因此，越来越多的医疗需求未得到满足。 选择性和有效的药物来治疗所有BCa亚型的早期和耐药阶段。 无论ER表达状态如何，BCa活力都依赖于广泛的表观遗传网络。 修饰剂-组蛋白标记写入器、读取器和擦除器。生物信息学和功能分析已经确定 组蛋白赖氨酸脱甲基酶（KDM）的氨基氧化酶和Jumonji家族的特定亚家族，组蛋白 甲基转移酶（HMT）和组蛋白脱乙酰酶（HDAC）在支持ERα信号传导中至关重要 activation.在这些表观遗传修饰因子中，KDM 1、KDM 3A、KDM 5A、KDM 5 B和KDM 6A是最重要的表观遗传修饰因子。 连接到ERα信号传导中，并且共同对BCa细胞活力至关重要。此外，研究表明， 如KDM 6A在其他ER非依赖性表观遗传重编程中也维持TNBC。不同于ERα KDM的药理学抑制尚未得到临床验证。虽然抑制KDM 3A， KDM 5A、KDM 5 B和KDM 6A在体内外均可引起BCa细胞生长停滞，但已有先例 用于在通过选择性缺失旁系成员产生的肿瘤模型中KDM旁系同源物之间进行补偿。 本研究假设，与BCa病因学有关的KDM旁系同源物的集体抑制将使BCa的表达减弱。 KDM旁系同源物之间的补偿可能发生在旁系选择性抑制中，导致 新的选择性和有效的药物来治疗BCa，而不管细胞ER表达状态如何。拟定研究 就是为了验证这个假设具体目标是：1）开发具有良好生物活性的Def基KDM抑制剂， 毒理学和药代动力学（PK）特性。2)表征细胞内靶向之间的相关性 作用（药效学）和全细胞抗增殖活性。3)研究电极导线的体内有效性 化合物在五种BCa鼠模型中的作用。

Project Summary/Abstract: In 2020 there will be ~ 276,480 estimated new cases of invasive breast cancer (BCa) among women in the US, causing an estimated ~ 42,170 deaths. Two common mechanisms for the sustenance of BCa are epigenetic dysfunction and the malfunction of endocrine proteins such as estrogen receptor (ER). The specific focus of the studies proposed in this application is to repurpose deferiprone (Def), an FDA-approved iron chelator, as a template for the discovery of novel histone lysine demethylase (KDM) inhibitors optimized for BCa therapy. Most compounds that have been or are being developed clinically exhibit greater efficacy for a subtype of BCa. In this regard, therapeutic interventions that capitalize on ER signaling malfunctions, a driver of more than 70% of BCas, have enjoyed measured success in BCa therapy and/or chemo- prevention. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these drugs. Additionally, there are no targeted treatment options for triple-negative breast cancer (TNBC), a BCa subtype lacking ER, Human Epidermal Growth Factor receptor 2 (HER2), and Progesterone Receptor (PR) and which accounts for over 20% of BCa incidence. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat early and resistant stages of all BCa subtypes. BCa viability, regardless of ER expression status, depends on an extensive network of epigenetic modifiers - histone mark writers, readers and erasers. Bioinformatic and functional analysis have identified specific subfamilies of the amino oxidase and Jumonji family of histone lysine demethylases (KDMs), histone methyltransferases (HMTs) and histone deacetylase (HDACs) as essential in supporting ERα signaling activation. Among these epigenetic modifiers, KDM1, KDM3A, KDM5A, KDM5B and KDM6A are exquisitely wired into ERα signaling and are collectively vital for BCa cell viability. Moreover, studies have implicated KDMs such as KDM6A in other ER-independent epigenetic reprograming which sustains TNBC as well. Unlike ERα signaling, pharmacological inhibition of KDMs has not been clinically validated. Although inhibition of KDM3A, KDM5A, KDM5B and KDM6A caused BCa cells growth arrest in vitro and in vivo, there are however precedents for compensation among KDM paralogs in tumor models generated by selective deletion of a paralog member. This study hypothesizes that collective inhibition of KDM paralogs implicated in BCa etiology will blunt the possibility of compensation among KDM paralogs that could occur from paralog selective inhibition, resulting in novel selective and potent drugs to treat BCa regardless of the cell ER expression status. The proposed study is designed to test this hypothesis. The specific aims are: 1) Develop Def-based KDM inhibitors with favorable toxicological and pharmacokinetic (PK) properties. 2) Characterize the correlation between intracellular on-target effects (pharmacodynamics) and whole cell antiproliferative activity. 3) Investigate the in vivo efficacy of lead compounds in five BCa murine models.