Inhibierung von HECT-Ligasen zur Krebstherapie

抑制 HECT 连接酶用于癌症治疗

• 批准号: 409480455
• 负责人: Professor Dr. Stefan Laufer
• 金额: --
• 依托单位: Fachrichtung Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409480455?language=en
• 关键词: Inhibierung; von; HECT; Ligasen; zur

Ubiquitination enzymes regulate countless physiological and disease-associated processes and have emerged as powerful targets on the drug discovery arena. Ubiquitin ligases (E3 enzymes) are particularly interesting points of therapeutic intervention. With an estimated 1000 members in the human proteome, the E3 family is the most diversified among the different classes of ubiquitination enzymes and mediates the recruitment of substrates for modification, thus providing key specificity determinants in ubiquitin signaling. HECT-type E3 enzymes contain a defined catalytic center and have historically been expected to be ‘druggable’. Surprisingly, however, few small-molecule discovery efforts targeting HECT E3 enzymes have been reported, despite crucial roles of these enzymes in human pathogeneses, including various types of cancer.During the first funding period of the Research Group Martin Eilers, Nikita Popov, and colleagues discovered that downregulation of the HECT E3 enzyme HUWE1 presents a therapeutic window in colorectal carcinoma. This work has also led to the identification of specific small-molecule inhibitors by high-throughput screening. Intriguingly, the identified compounds were found to block MYC-dependent transcriptional activation in colorectal cancer cells, but not in stem and normal colon epithelial cells. These selective effects could be pinpointed to the stabilization of a particular substrate of HUWE1, the transcription factor MIZ1, that can form repressive complexes with MYC. Building on these proof-of-principle results, we aim to uncover the molecular basis of the identified inhibitors, utilize this knowledge for the development of optimized compounds, and subject them to in vivo analyses. These studies will go hand-in-hand with a systematic interrogation of the precise roles of HUWE1 during homeostasis and tumor maintenance – a vital prerequisite for exploiting the activity of this ligase therapeutically. To accomplish this research plan we will bundle our structural (Sonja Lorenz), medicinal-chemical (Stefan Laufer), and cell biological (Nikita Popov) expertise. Additional synergies will arise from interactions with other members of the Research Group, particularly Martin Eilers (biology of HUWE1 in MYC-mediated transcriptional regulation), Lars Zender (mosaic mouse models), Armin Wiegering (patient-derived organoids), Antti Poso (docking), and Andreas Rosenwald (histopathology service). We are therefore in an excellent position to define the therapeutic window that HUWE1 presents in cancer therapy, thereby providing unprecedented evidence for the accessibility of HECT E3 enzymes to specific small-molecule inhibition in vivo.

泛素化酶调节无数生理和疾病相关过程，并已成为药物发现领域的强大靶点。泛素连接酶（E3酶）是特别有趣的治疗干预点。在人类蛋白质组中估计有1000个成员，E3家族是不同类别的泛素化酶中最多样化的，并介导底物的修饰募集，从而为泛素信号传导提供关键的特异性决定因素。hect型E3酶含有一个明确的催化中心，历史上一直被认为是“可药物化”的。然而，令人惊讶的是，尽管这些酶在人类发病机制（包括各种类型的癌症）中起着至关重要的作用，但很少有针对HECT E3酶的小分子发现的报道。在研究小组的第一个资助期内，Martin Eilers、Nikita Popov及其同事发现HECT E3酶HUWE1的下调为结直肠癌提供了一个治疗窗口。这项工作还通过高通量筛选鉴定了特定的小分子抑制剂。有趣的是，发现鉴定的化合物可以阻断结直肠癌细胞中myc依赖的转录激活，但在干细胞和正常结肠上皮细胞中却没有。这些选择性效应可以确定为HUWE1的特定底物的稳定，转录因子MIZ1，可以与MYC形成抑制复合物。在这些原理验证结果的基础上，我们的目标是揭示已鉴定抑制剂的分子基础，利用这些知识开发优化的化合物，并对其进行体内分析。这些研究将与HUWE1在体内平衡和肿瘤维持过程中的精确作用的系统研究携手并进——这是利用这种连接酶的活性进行治疗的重要先决条件。为了完成这项研究计划，我们将结合我们的结构（索尼娅·洛伦兹）、药物化学（斯特凡·劳弗）和细胞生物学（尼基塔·波波夫）专业知识。额外的协同效应将来自与研究小组其他成员的互动，特别是Martin Eilers （HUWE1在myc介导的转录调节中的生物学），Lars Zender（马赛克小鼠模型），Armin Wiegering（患者来源的类器官），Antti Poso（对接）和Andreas Rosenwald（组织病理学服务）。因此，我们处于一个很好的位置，可以定义HUWE1在癌症治疗中的治疗窗口，从而为HECT E3酶在体内特异性小分子抑制的可及性提供前所未有的证据。