通过表型筛选发现 YAP1/TAZ 通路抑制剂,这些抑制剂通过阻断 Rho-GTPase 信号传导具有强大的抗肿瘤活性。

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

摘要

本研究介绍了对体内具有强效抗肿瘤活性的致癌性Yes-associated蛋白(YAP1)/TAZ活性小分子抑制剂的鉴定和靶点解构。利用细胞 YAP1/TAZ 报告实验对 380 万个化合物进行了高通量筛选 (HTS)。靶点解卷积研究发现,geranylgeranyltransferase-I(GGTase-I)复合物是 YAP1/TAZ 通路抑制剂的直接靶点。小分子抑制剂可阻断 Rho-GTP 酶的活化,从而导致 YAP1/TAZ 失活,抑制体外癌细胞增殖。经过多参数优化后,BAY-593 成为一种体内探针,具有良好的 PK 特性,在体内显示出抗肿瘤活性并阻断 YAP1/TAZ 信号传导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling

Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.

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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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