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

描述（由申请人提供）：羧基末端结合蛋白（Carboxyl-terminal binding protein, CtBP）是许多转录因子的协同抑制因子，最初被认为是一种腺病毒e1a结合蛋白。在大多数成人组织中，CtBP表达低或检测不到。我们发现CtBP在多种人类癌症中异常过表达。例如，它在50%以上的原发性肺癌和90%的转移性病变中过表达。我们还观察到CtBP在乳腺肿瘤、头颈癌、肾癌和黑色素瘤中频繁过表达。我们发现CtBP过表达会抑制细胞死亡关键基因的表达，从而导致癌症的发生。此外，我们在小鼠模型中发现，降低肺癌细胞中的CtBP可诱导癌细胞死亡，并抑制人类肿瘤生长。基于这些数据，我们假设降低CtBP的功能代表了一种有吸引力的治疗多种癌症类型且副作用有限的方法。CtBP与E1A和

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.