河马信号通路
癌症研究
梅林(蛋白质)
转录因子
细胞生长
间皮瘤
生物
细胞生物学
雅普1
基因
信号转导
遗传学
抑制器
医学
病理
作者
Tracy Tang,Andrei W. Konradi,Zhiqin Chen,Xiao Peng,Mingyue Ma,Jian Li,Fa‐Xing Yu,Kun‐Liang Guan,Leonard Post
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2021-04-13
卷期号:20 (6): 986-998
被引量:94
标识
DOI:10.1158/1535-7163.mct-20-0717
摘要
Abstract Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo. These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases. Watch the interview with Tracy T. Tang, PhD, recipient of the 2023 Molecular Cancer Therapeutics Award for Outstanding Journal Article: https://vimeo.com/847434464
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