Development of small molecules for ERG ablation in prostate cancer

开发用于前列腺癌 ERG 消融的小分子

基本信息

批准号：
9005588
负责人：
Ralf Kittler
金额：
$ 36.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-08 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005588
关键词：
AR gene Ablation Address Adverse effects Affect Amino Acids Androgen Receptor Androgens Attenuated Cell Culture Techniques Cell Line Cells Cessation of life Chemicals Clinical Trials Data Deubiquitinating Enzyme Deubiquitination Development Disease Drug Targeting Effectiveness Enzyme Inhibition Enzymes Future Gene Expression Gene Fusion Gene Proteins Generations Genes Goals Growth Human Incidence Lead Libraries Malignant Neoplasms Malignant neoplasm of prostate Measures Messenger RNA Modeling Molecular Mus New Agents Oncogenic Patients Pre-Clinical Model Preclinical Testing Preparation Property Prostatic Neoplasms Proteins Proteome Receptor Signaling Refractory Research Research Proposals Resistance development Serine Protease Specificity Stable Isotope Labeling System Testing Therapeutic Therapeutic Agents Toxic effect Ubiquitination United States VCaP Work Xenograft procedure analog base cancer therapy castration resistant prostate cancer design enzyme activity improved in vivo inhibitor/antagonist knock-down male men molecular targeted therapies novel novel therapeutic intervention overexpression pre-clinical prostate cancer cell prostate cancer cell line prostate cancer model protein expression public health relevance relapse patients response screening small molecule small molecule inhibitor targeted agent targeted treatment transcription factor tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy in men and the second leading cause of male cancer-related death in the United States. The main focus of targeted molecular therapies in advanced prostate cancer has been the androgen receptor signaling. While first- and second generation drugs that target androgen receptor signaling have efficacy and have increased overall survival, most patients relapse with tumors that are refractory to these treatments. More effective monotherapies targeting androgen receptor signaling are in development but are unlikely to achieve durable responses, due to the development of resistance. Thus, there is a critical need for agents targeting alternative molecular drivers of prostate cancer. The transcription factor Ets Related Gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene Transmembrane protease, serine 2 (TMPRSS2) in ~ 50% of advanced prostate tumors, is a key driver of prostate cancer development and progression. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. We hypothesize that ERG stability in prostate cancer cells is modulated by the interplay of ubiquitination and deubiquitination, and that the proteins regulating the ubiquitinatin state of ERG may include enzymes that can be therapeutically targeted with small molecule inhibitors. We recently found that (1) the deubiquitinase USP9X stabilizes ERG, (2) the deubiquitinase inhibitor WP1130 causes a rapid increase of ubiquitinated ERG, which results in ERG depletion, (3) WP1130 inhibits the growth of ERG-expressing prostate tumors in vivo, and (4) a novel analog KRL-113 has better potency than WP1130 in targeting ERG. In this research proposal, we seek to build on our work to identify, characterize and optimize small molecules that cause ERG depletion, and to evaluate small molecule inhibitors affecting ERG turnover in preclinical models. To accomplish these aims, we will use rational design to further optimize the ERG-ablating compound KRL-113 in order to improve its pharmacological efficacy and specificity. In parallel, we will screen a chemical compound library to identify additional lead compounds that reduce ERG protein levels. We will characterize the effects of optimized KRL-113 analogs and new lead compounds on the proteome of prostate cancer cells. Finally, we will test the ability of KRL-113 and its analogs to reduce ERG protein levels and inhibit tumor growth in both mouse xenograft and human primary prostate tumor explant models.

描述（由申请人提供）：前列腺癌是男性最常见的恶性肿瘤，也是美国男性癌症相关死亡的第二大原因。晚期前列腺癌的靶向分子治疗的主要焦点是雄激素受体信号传导。虽然针对雄激素受体信号传导的第一代和第二代药物具有疗效并提高了总体生存率，但大多数患者的肿瘤对这些治疗无效，目前正在开发更有效的针对雄激素受体信号传导的单一疗法，但不太可能实现。因此，迫切需要针对前列腺癌的替代分子驱动因子的药物，该基因通过与雄激素反应基因跨膜融合而过度表达。蛋白酶丝氨酸 2 (TMPRSS2) 存在于约 50% 的晚期前列腺肿瘤中，是前列腺癌发生和进展的关键驱动因素，消除 ERG 会破坏关键的致癌转录回路，并可能导致前列腺癌的发生。我们发现前列腺癌细胞中的 ERG 稳定性是通过泛素化和去泛素化的相互作用来调节的，并且调节 ERG 泛素化状态的蛋白质可能包括可以用小分子作为治疗靶点的酶。我们最近发现 (1) 去泛素酶 USP9X 可以稳定 ERG，(2) 去泛素酶抑制剂 WP1130 会导致 ERG 快速增加。泛素化 ERG，导致 ERG 耗竭，(3) WP1130 抑制体内表达 ERG 的前列腺肿瘤的生长，(4) 新型类似物 KRL-113 在靶向 ERG 方面比 WP1130 具有更好的效力。寻求在我们的工作基础上识别、表征和优化导致 ERG 耗竭的小分子，并评估影响临床前模型中 ERG 周转的小分子抑制剂。为了实现这些目标，我们将使用合理的设计来进一步优化 ERG 消融化合物 KRL-113，以提高其药理功效和特异性。同时，我们将筛选化合物库，以确定降低 ERG 蛋白水平的其他先导化合物。我们将表征优化的 KRL-113 类似物和新的先导化合物对前列腺癌细胞蛋白质组的影响。最后，我们将测试 KRL-113 及其类似物降低 ERG 蛋白水平和抑制肿瘤生长的能力。小鼠异种移植和人类原发性前列腺肿瘤外植体模型。