Identify inhibitors of the Six1/Eya interaction using high throughput screening

描述(申请人提供)：SIX1是一种发育基因，在很大比例的乳腺癌中异常重新表达。这种过度表达在乳腺癌的发生和转移发展中起着因果作用。由于SIX1没有自己的激活或抑制结构域，Eya家族的SIX1共激活蛋白在SIX1介导的乳腺肿瘤的发生和转移中是必不可少的。我们已经开发了一种基于AlphaScreen的针对SIX1/Eya相互作用的HTS分析方法。我们建议使用NIH MLPCN化合物进行大规模高通量筛选，以确定SIX1/EYA相互作用的抑制剂。我们计划测试这些抑制剂作为治疗工具的潜力，以抑制SIX1介导的乳腺肿瘤发生和转移。这些抑制剂也可以作为有价值的化学探针用于涉及SIX1/EYA相互作用的研究。 公共卫生相关性：SIX1是一种转录因子，对大部分乳腺肿瘤的发生和发展以及肝细胞癌和横纹肌肉瘤的转移至关重要。Eya2是SIX1的共同激活因子，在SIX1介导的肿瘤发生和转移中起着至关重要的作用。该项目旨在通过高通量筛选来识别SIX1/EYA相互作用的小分子抑制剂，用于抗癌治疗。由于SIX1在50%的原发乳腺肿瘤和90%的转移性病变中过表达，我们预计这项工作可能会使大量乳腺癌患者以及患有过表达SIX1和/或EYA的其他类型肿瘤的患者受益。

DESCRIPTION (provided by applicant): Six1 is a developmental gene that is abnormally re-expressed in a large percentage of breast cancers. This over-expression plays a causal role in the initiation and metastatic development of breast cancers. Since Six1 does not have its own activation or repression domain, the Eya family of Six1 co-activator proteins is essential for Six1-mediated breast tumorigenesis and metastasis. We have developed an AlphaScreen based HTS assay targeting the Six1/Eya interaction. We propose to perform a large scale high throughput screening using the NIH MLPCN compounds to identify inhibitors of the Six1/Eya interaction. We plan to test these inhibitors for their potential as therapeutic tools to inhibit Six1-mediated breast tumorigenesis and metastasis. These inhibitors can also be used as valuable chemical probes for studies involving the Six1/Eya interaction. PUBLIC HEALTH RELEVANCE: Six1 is a transcription factor that is critical for the onset and progression of a large percentage of breast tumors, as well as for metastasis of hepatocellular carcinoma and rhabdomyosarcoma. Eya2 is a co-activator of Six1 that is essential for Six1-mediated tumorigenesis and metastasis. This project intends to identify small molecule inhibitors of the Six1/Eya interaction using high throughput screening for anti-cancer therapy. Because Six1 is overexpressed in 50% of primary breast tumors and 90% of metastatic lesions, we expect this work to potentially benefit a large population of breast cancer patients, as well as patients that harbor other types of tumors that overexpress Six1 and/or Eya.