Identification of potent and selective GLI1 inhibitors

有效且选择性 GLI1 抑制剂的鉴定

基本信息

批准号：
8523361
负责人：
Kevin Peter Williams
金额：
$ 28.99万
依托单位：
ZEN-BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2014-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523361
关键词：
Affect Animal Model Apoptosis Biological Assay Biological Factors Biological Models Breast Cancer Model Cancer cell line Cell Line Cell Survival Cells Characteristics Chemicals Clinic Clinical Collection Colon Colon Carcinoma Development Dose Embryonic Development Erinaceidae Esophageal Exclusion Family Feedback Firefly Luciferases GLI gene Growth Human Image In Vitro Light Lung Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of ovary Mammary Gland Parenchyma Mammary Neoplasms Measures Mediator of activation protein Mitotic Nuclear Translocation Pancreas Pathway interactions Patients Pharmaceutical Chemistry Phenotype Play Preclinical Drug Evaluation Prostate Proteins Regulation Reporter Reporting Resistance Role Sampling Series Signal Transduction Structure-Activity Relationship Therapeutic Time Tissues Toxic effect analog annexin A5 base cancer cell cancer type cell growth cell motility cost effective cyclopamine high throughput screening in vivo inhibitor/antagonist innovation malignant breast neoplasm neoplastic cell novel overexpression promoter public health relevance scaffold screening small molecule smoothened signaling pathway therapeutic target tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Characterization of human tumor samples and cell lines in combination with inhibitor studies in animal models has established a central role for the Hh pathway in a vast array of cancer types, including small-cell lung, pancreatic, oesophageal, prostate, breast, colon, liver and ovarian cancers. Hh signaling is now implicated in approximately 20-25% of all cancers. GLI1 is the downstream effector in the Hh signaling pathway, and has emerged as a valid therapeutic target. It has been suggested that due to the complexity of signaling inputs in the Hh pathway, targeting GLI1 may provide a more comprehensive strategy for treating both canonical and noncanonical Hh-pathway dependent cancers. This is especially true in light of the acquired resistance to inhibitors of SMO in patients. Screens utilizing GLI1-dependent transcriptional reporter cell-based assays have yielded inhibitors targeting the Hh pathway downstream of SMO including small molecule and natural product compounds that act by targeting GLI1 through differing mechanisms of action. Targeting at the level of GLI1 with small molecules has been effective in a number of cancer model systems including colon, CLL and breast cancer. However, these compounds have only micromolar potencies in vitro, and a subset (GANT61 and ATO) has shown only modest efficacy in in vivo cancer models. These studies suggest that GLI1 is pharmacologically targetable, and that the use of GLI1 inhibitors is a valid and promising approach for targeting GLI1-dependent cancers. Unfortunately, current GLI1 inhibitors are hampered by low potency and a lack of in vivo efficacy and hence are not viable clinical candidates. There are no GLI1-targeted inhibitors in the clinic. Using a novel high throughput, high content cell-based imaging platform, we will screen a diverse collection of small molecules to identify potent inhibitors of GLI1 (Aim 1). Compounds that show inhibitory activity will be further validated in a focused panel of cell-based assays which will incorporate cells derived from primary human breast tumors. These assays will also examine selectivity of the compounds as well as their effects on motility/invasiveness (Aim 2). Promising compounds discovered in Aims 1 and 2 will be subjected to extensive structure-activity relationship to optimize the novel GLI1 inhibitors (Aim 3).

描述（由申请人提供）：人类肿瘤样品和细胞系的表征与动物模型中的抑制剂研究相结合，已确立了该研究的核心作用。 Hh 通路存在于多种癌症类型中，包括小细胞肺癌、胰腺癌、食道癌、前列腺癌、乳腺癌、结肠癌、肝癌和卵巢癌。目前，Hh 信号传导与大约 20-25% 的癌症有关。 GLI1 是 Hh 信号通路的下游效应子，已成为有效的治疗靶点。有人建议，由于 Hh 通路中信号输入的复杂性，靶向 GLI1 可能为治疗典型和非典型 Hh 通路依赖性癌症提供更全面的策略。鉴于患者对 SMO 抑制剂产生了耐药性，这一点尤其如此。利用基于 GLI1 的转录报告基因细胞测定进行的筛选已产生针对 SMO 下游 Hh 通路的抑制剂，包括通过不同作用机制靶向 GLI1 的小分子和天然产物化合物。用小分子靶向 GLI1 水平在许多癌症模型系统中都有效，包括结肠癌、慢性淋巴细胞白血病和乳腺癌。然而，这些化合物在体外仅具有微摩尔效力，并且其中一个子集（GANT61 和 ATO）在体内癌症模型中仅显示出适度的功效。这些研究表明，GLI1 具有药理学靶向性，并且使用 GLI1 抑制剂是针对 GLI1 依赖性癌症的有效且有前景的方法。不幸的是，目前的 GLI1 抑制剂由于效力低且缺乏体内功效而受到阻碍，因此不是可行的临床候选药物。临床上尚无针对GLI1的抑制剂。使用新型高通量、高内涵细胞成像平台，我们将筛选多种小分子，以鉴定 GLI1 的有效抑制剂（目标 1）。显示抑制活性的化合物将在基于细胞的集中检测中得到进一步验证，该检测将纳入来自原发性人类乳腺肿瘤的细胞。这些测定还将检查化合物的选择性及其对运动性/侵袭性的影响（目标 2）。目标 1 和 2 中发现的有前景的化合物将受到广泛的结构-活性关系的影响，以优化新型 GLI1 抑制剂（目标 3）。