Reposition and Optimization of Deferiprone for Breast Cancer Therapy

去铁酮在乳腺癌治疗中的重新定位和优化

基本信息

批准号：
10576342
负责人：
Adegboyega Oyelere
金额：
$ 53.22万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576342
关键词：
4T1 Apoptosis Bioinformatics Breast Cancer Cell Breast Cancer cell line Breast Cancer therapy Breast Carcinoma Cancer Cell Growth Cancer Etiology Cell Survival Cells Cessation of life Chemoprevention Clinical Compensation Data Drug Kinetics Drug resistance Endocrine Epidermal Growth Factor Receptor Epigenetic Process Estrogen Receptor Modulators Estrogen Receptor alpha Estrogen Receptors Exhibits FDA approved Family Fulvestrant Functional disorder Heterochromatin Histone Deacetylase Histones Hormones Human In Vitro Incidence Investigation Iron Chelation KDM5B gene Lead Lysine MDA MB 231 Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Medical Modality Modeling Neoplasm Metastasis Oxidases Patients Pharmaceutical Preparations Pharmacodynamics Positioning Attribute Progesterone Receptors Property Proteins Reader Receptor Signaling Relapse Resistance Role Signal Transduction T47D Tail Tamoxifen Testing Therapeutic Agents Therapeutic Intervention Toxicology Veins Woman Xenograft procedure antagonist cancer subtypes clinical development cytotoxic cytotoxicity design gene repression histone methyltransferase in vivo inhibitor insight lead candidate malignant breast neoplasm member mouse model neoplastic cell novel novel therapeutics paralogous gene pharmacologic preclinical study receptor expression success targeted treatment triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

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.

项目摘要/摘要：2020年将有〜276,480估计的新病例侵入性乳腺癌病例（BCA）在美国妇女中，估计约42,170人死亡。两个共同的机制 BCA的寄生是表观遗传功能障碍和内分泌蛋白（例如雌激素）的故障接收器（ER）。本应用中提出的研究的具体重点是复制脱脂酮（DEF），， FDA批准的铁螯合剂，作为新型组蛋白赖氨酸脱甲基酶（KDM）的模板为BCA治疗优化的抑制剂。大多数已经或正在开发的化合物在临床上展出 BCA亚型的效率更高。在这方面，利用ER信号传导的治疗干预措施故障是BCA的70％以上的驱动因素，在BCA疗法和/或化学疗法方面取得了成功预防。但是，目的地初始好处，大多数患者最终由于对这些的抗药性而继承了毒品。此外，没有针对三阴性乳腺癌（TNBC）的靶向治疗选择，即BCA 缺乏ER的亚型，人类表皮生长因子受体2（HER2）和孕酮受体（PR）和占BCA事件的20％以上。因此，越来越多的医疗需求选择性和潜在药物以治疗所有BCA亚型的早期和抗性阶段。 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符 - Hisstone Mark作家，读者和橡皮擦。生物信息学和功能分析已经确定组蛋白赖氨酸脱甲基酶（KDMS），组蛋白的氨基氧化物和Jumonji家族的特定亚家族甲基转移酶（HMTS）和Hisstone脱乙酰基酶（HDAC）对于支持ERα信号至关重要激活。在这些表观遗传修饰符中，KDM1，KDM3A，KDM5A，KDM5B和KDM6A恰好是连接到ERα信号传导中，对BCA细胞活力至关重要。此外，研究已经实施了KDM 例如其他与ER无关的表观遗传重编程中的KDM6A，也可以维护TNBC。与ERα不同信号传导，KDMS的药理抑制尚未在临床上进行验证。尽管抑制KDM3A，但 KDM5A，KDM5B和KDM6A引起BCA细胞在体外和体内的生长停滞，但是有先例通过选择性删除旁系同源成员产生的肿瘤模型中的KDM旁系同源物之间的补偿。这项研究假设BCA病因中实施的KDM旁系同源物的集体抑制作用将钝化 KDM旁系同源物中可能会因旁系同源物选择性抑制而发生补偿的可能性，从而导致无论细胞ER的表达状态如何，新型的选择性和潜在药物都可以治疗BCA。拟议的研究旨在检验这一假设。具体目的是：1）开发基于DEF的KDM抑制剂毒理学和药代动力学（PK）特性。 2）表征细胞内靶标之间的相关性作用（药效学）和全细胞抗增生活性。 3）研究铅的体内效率五种BCA鼠模型中的化合物。