Reposition and Optimization of Deferiprone for Breast Cancer Therapy

项目摘要/摘要：2020年估计将有大约276,480例浸润性乳腺癌新病例 (BCA)在美国女性中传播，估计造成约42,170人死亡。有两种常见的机制用于 BCA的维持是表观遗传功能障碍和雌激素等内分泌蛋白功能障碍 受体(ER)。本申请中提出的研究的具体焦点是重新调整去铁酮(Def)的用途， FDA批准的铁络合剂，作为发现新组蛋白赖氨酸去甲基酶(KDM)的模板 针对BCA治疗进行了优化的抑制剂。大多数已经或正在开发的化合物在临床上表现出 对BCA的亚型有更好的疗效。在这方面，利用ER信号的治疗干预 故障是BCA的70%以上的驱动因素，在BCA治疗和/或化疗方面取得了一定的成功。 预防。然而，尽管最初有好处，但由于对这些药物的获得性耐药性，大多数患者最终会复发 毒品。此外，三阴性乳腺癌(TNBC)是一种BCA，目前还没有针对性的治疗选择 缺乏ER、人表皮生长因子受体2(HER2)和孕激素受体(PR)的亚型和 占BCA发病率的20%以上。因此，有一种未得到满足的医疗需求日益增长 治疗所有BCA亚型的早期和耐药阶段的选择性和强效药物。 BCA的生存能力，无论ER表达状态如何，都取决于广泛的表观遗传网络 修饰语--组蛋白标记作者、读者和橡皮擦。生物信息学和功能分析已经确定 氨基氧化酶和组蛋白赖氨酸去甲基酶Jumonji家族的特定亚家族，组蛋白 甲基转移酶(HMTs)和组蛋白脱乙酰酶(HDACs)在支持ERα信号转导中的作用 激活。在这些表观遗传修饰剂中，KDM1、KDM3A、KDM5A、KDM5B和KDM6A是精致的 连接到内质网α信号，共同对大脑中动脉细胞的生存至关重要。此外，研究表明KDM与 例如KDM6A在其他ER非依赖的表观遗传重新编程中，也支持TNBC。与ERα不同 KDMS的信号、药理抑制作用尚未得到临床验证。虽然抑制KDM3A， KDM5A、KDM5B和KDM6A在体内外引起BCA细胞生长停滞，但也有先例 用于在通过选择性删除平行对数成员而产生的肿瘤模型中的KDM平行对数之间进行补偿。 这项研究假设，集体抑制与BCA病因学有关的KDM旁系基因将钝化 在KDM并列动物之间可能发生的补偿可能发生在PARALOG选择性抑制中，导致 治疗BCA的新型选择性和强效药物，与细胞ER表达状态无关。建议进行的研究 旨在检验这一假说。具体目标是：1)研制具有良好抗炎活性的DEF类KDM抑制剂 毒理学和药代动力学(PK)特性。2)表征细胞内目标上的相关性 作用(药效学)和全细胞抗增殖活性。3)研究铅的体内效应 五种BCA小鼠模型中的化合物。

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.