Identification and development of inhibitors of the Hippo-Yap pathway

 描述(由申请人提供)：Hippo-Yap信号通路已成为多种人类恶性肿瘤发生和转移的主要驱动因素。该途径的远端效应物YAP，作为转录激活因子，驱动促增殖和抗凋亡基因的表达。重要的是，几种肿瘤类型依赖于YAP，包括结直肠、肝细胞、脑膜瘤、间皮瘤和神经鞘瘤。几项研究强烈支持这样一种观点，即抑制Hippo-YP途径将在广泛的癌症类型中显示出有效性。我们的长期目标是确定河马-YAP途径的小分子抑制剂，这些小分子抑制剂可以开发成治疗依赖河马-YAP的癌症的药物。为了获得有效的先导化合物，选择性地抑制YAP驱动的转录，我们将利用斯克里普斯药物发现文库实施超高通量筛选活动。将在一系列二次筛选中对已确定的线索进行评估，并将使用结构活性关系分析和药物化学来根据其类似药物的特性来优化和优先排序线索。Top Leads将用于作用机制研究，并在YAP依赖肿瘤的细胞模型中进行测试，包括脑膜瘤和神经鞘瘤细胞，以确定选定化合物对肿瘤细胞生长和存活的影响。拟议的研究活动将确定安全和有效的先导化合物，这些化合物将在体内进行测试，并将适合临床使用。 发展将被确定为治疗学。这些研究应该能够识别出对YAP依赖的广泛人类肿瘤有效的精选先导。

 DESCRIPTION (provided by applicant): The Hippo-YAP signaling pathway has emerged as a major driver of tumorigenesis and metastasis in a wide spectrum of human malignancies. The distal effector of the pathway - YAP, functions as a transcriptional activator driving expression of pro-proliferation and anti- apoptotic genes. Importantly, several tumor types are YAP dependent, including colorectal, hepatocellular, meningioma, mesothelioma and schwannoma. Several studies strongly promote the notion that inhibiting the Hippo-YP pathway will show efficacy in a broad spectrum of cancer types. Our long-term goal is to identify small molecule inhibitors of the Hippo-Yap pathway that can be developed into therapeutic agents for the treatment of cancers that are Hippo- YAP dependent. To obtain potent lead compounds that selectively inhibit YAP-driven transcription we will implement an ultra High Throughput Screening campaign using the Scripps Drug Discovery Library. Identified leads will assessed in a series of secondary screens and Structure Activity Relationship analysis and medicinal chemistry will be used to optimize and prioritize leads based on their drug-like properties. Top leads will be used in mechanism of action studies and tested in cell-based models of YAP-dependent tumors including meningioma and schwannoma cells to determine the effects of select compounds on tumor cell growth and survival. The proposed research campaign will identify safe and potent lead compounds that will be tested in vivo and leads suitable for clinical development as therapeutics will be identified. These studies should result in identification of select leads demonstrating efficacy against a broad spectrum of human tumors which are YAP-dependent involvement.