Hippo pathway inhibition by blocking the YAP/TAZ-TEAD interface: a patent review
Hippo pathway inhibition by blocking the YAP/TAZ-TEAD interface: a patent review
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DOI：
10.1080/13543776.2018.1549226
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发表时间：
2018-12-02
影响因子：
6.6
通讯作者：
Zbieg, Jason R.
中科院分区：
文献类型：
--
作者：
Crawford, James J.;Bronner, Sarah M.;Zbieg, Jason R.
简介：Hippo通路代表了治疗癌症的一个新的和有趣的机会。已证明，激活或过表达的Yes相关蛋白（雅普）或转录辅激活因子与PDZ结合基序（TAZ）导致细胞转化和肿瘤的发展。迄今为止，还没有靶向该途径的小分子化合物进入临床，这说明了其潜力和初期阶段。涵盖的领域：本综述旨在总结受让人公司已公开的雅普/TAZ-转录增强相关结构域（TEAD）相互作用的直接小分子抑制剂的专利申请。专家意见：Hippo途径，特别是雅普/TAZ-TEAD转录复合物，已被证明是治疗癌症的有希望的靶标。然而，靶向雅普/TAZ-TEAD转录激活复合物的小分子领域的报道很少，只有两个公开的专利申请公开了具有中等水平的途径抑制的化合物。有趣的是，雅普/TAZ-TEAD复合物可以通过两种非常不同的机制被破坏，其中之一是直接抑制YAP-TEAD结合界面的ω-环或α-螺旋。两个雅普蛋白片段已被证明对TEAD结合是重要的。或者，据报道，变构抑制可以通过结合TEAD棕榈酰化口袋，从而破坏雅普结合以及天然蛋白质稳定来实现。通过这两种不同的机制破坏雅普/TAZ-TEAD复合物的优点和缺点尚未完全阐明，并且仍然不清楚哪种方法（如果有的话）将产生Hippo途径的第一个临床阶段抑制剂。
Introduction: The Hippo pathway represents a new and intriguing opportunity for the treatment of cancer. Activation or overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) has been shown to lead to cell transformation and tumor development. To date, no small molecule compounds targeting this pathway have progressed to the clinic, illustrating both its potential and its infancy. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed direct small molecule inhibitors of the YAP/TAZ-transcriptional enhanced associate domain (TEAD) interaction. Expert opinion: The Hippo pathway, and specifically the YAP/TAZ-TEAD transcriptional complex, has been shown to be a promising target for the treatment of cancer. However, reports in the area of small molecules targeting the YAP/TAZ-TEAD transcriptional activation complex are few and far between, with only two published patent applications that disclose compounds with moderate levels of pathway inhibition. Interestingly, the YAP/TAZ-TEAD complex can be disrupted through two very different mechanisms, one of which is direct inhibition at either the omega-loop or the alpha-helix of the YAP-TEAD binding interface. Both YAP protein segments have been shown to be important to TEAD binding. Alternatively, it has been reported that allosteric inhibition might be accomplished by binding the TEAD palmitoylation pocket, thus disrupting YAP binding and also native protein stabilization. The advantages and liabilities of disrupting the YAP/TAZ-TEAD complex through these two distinct mechanisms have yet to be fully elucidated, and it remains unclear which approach, if any, will generate the first clinical stage inhibitor of the Hippo pathway.