Identify Inhibitors of the Transcriptional Co-Repressor CtBP Using HTS for Cancer

描述(申请人提供)：羧基末端结合蛋白(CtBP)是许多转录因子的共抑制因子，最初被认为是腺病毒E1a结合蛋白。CTBP在大多数成人组织中的表达很低或检测不到。我们发现CtBP在多种人类癌症中异常过度表达。例如，在超过50%的原发肺癌和90%的转移性病变中，它过表达。我们还观察到CtBP在乳腺癌、头颈癌、肾癌和黑色素瘤中频繁的过度表达。我们发现CtBP的过度表达抑制了细胞死亡的关键基因的表达，从而导致癌症的发展。此外，我们在小鼠模型中发现，降低肺癌细胞中的CtBP可以诱导癌细胞死亡，并抑制人类肿瘤的生长。基于这些数据，我们假设降低CtBP的功能代表了一种具有吸引力的治疗多种癌症类型的方法，副作用有限。CTBP与E1a相互作用 其他转录因子通过一个保守的多肽基序。详细的生化/结构研究表明，使用小分子化合物来抑制CtBP与其结合的转录因子之间的相互作用是可行的。我们已经开发了一种基于Alpha Screen的HTS分析方法，针对CtBP/E1A相互作用。我们建议使用NIH MLPCN化合物进行大规模高通量筛选，以确定CtBP与其结合的转录因子之间相互作用的抑制剂。我们计划测试这些抑制剂作为治疗工具的潜力，以抑制CtBP介导的肿瘤发生和转移。这些抑制剂也可作为研究CtBP功能的有价值的化学探针。

DESCRIPTION (provided by applicant): Carboxyl-terminal binding protein (CtBP) is a co-repressor for many transcription factors and was initially recognized as an adenoviral E1A-binding protein. CtBP expression is low or undetectable in most adult tissues. We found that CtBP is abnormally over expressed in multiple human cancers. For example, it is over- expressed in over 50% of primary lung cancer and 90% of metastatic lesions. We also observed frequent CtBP over-expression in breast tumor, head and neck cancer, renal carcinoma, and melanoma. We have found that CtBP over expression suppresses the expression of genes critical for cell death, leading to cancer development. Moreover, we found that reducing CtBP in lung cancer cells induced cancer cell death, and suppressed human tumor growth in a mouse model. Based on these data, we hypothesize that decreasing CtBP's function represents an attractive therapy for multiple cancer types with limited side effects. CtBP interacts with E1A and other transcription factors through a conserved peptide motif. Detailed biochemical/structural studies reveal that it is feasible to use small molecule compounds to inhibit the interaction between CtBP and the transcription factors it binds. We have developed an Alpha Screen based HTS assay targeting the CtBP/E1A interaction. We propose to perform a large scale high throughput screening using the NIH MLPCN compounds to identify inhibitors of the interaction between CtBP and the transcription factors it binds. We plan to test these inhibitors for their potential as therapeutic tools to inhibit CtBP-mediated tumor genesis and metastasis. These inhibitors can also be used as valuable chemical probes for functional studies of CtBP.