Antiproliferative and Antimigratory Effects of a Novel YAP-TEAD Interaction Inhibitor Identified Using in Silico Molecular Docking

被引：72

作者：

Smith, Sarah A. ^{[1
]}

Sessions, Richard B. ^{[2
]}

Shoemark, Deborah K. ^{[2
]}

Williams, Christopher ^{[3
]}

Ebrahimighaei, Reza ^{[1
]}

McNeill, Madeleine C. ^{[1
]}

Crump, Matthew P. ^{[3
]}

McKay, Tristan R. ^{[4
]}

Harris, Gemma ^{[5
]}

Newby, Andrew C. ^{[1
]}

Bond, Mark ^{[1
]}

机构：

[1] Univ Bristol, Fac Hlth Sci, Sch Translat Hlth Sci, Bristol Royal Infirm, Res Floor,Level 7, Bristol BS2 8HW, Avon, England

[2] Univ Bristol, Fac Biomed Sci, Sch Biochem, Biomed Sci Bldg, Bristol BS8 1TD, Avon, England

[3] Univ Bristol, Fac Sci, Sch Chem, Bristol BS8 1TS, Avon, England

[4] Manchester Metropolitan Univ, Ctr Biosci, John Dalton Bldg, Manchester M1 5GD, Lancs, England

[5] Rutherford Appleton Lab, Res Complex Harwell, Harwell Campus, Didcot OX11 0FA, Oxon, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 03期

基金：

英国生物技术与生命科学研究理事会;

关键词：

YES-ASSOCIATED PROTEIN; ORGAN SIZE CONTROL; CELL-PROLIFERATION; HIPPO PATHWAY; TRANSCRIPTION FACTORS; CONTACT INHIBITION; SIGNALING PATHWAY; CANCER; EXPRESSION; GENE;

D O I：

10.1021/acs.jmedchem.8b01402

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

The Hippo pathway is an important regulator of cell growth, proliferation, and migration. TEAD transcription factors, which lie at the core of the Hippo pathway, are essential for regulation of organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) have been implicated in numerous human cancers and hyperproliferative pathological processes. Hence, the YAP TEAD complex is a promising therapeutic target. Here, we use in silico molecular docking using Bristol University Docking Engine to screen a library of more than 8 million druglike molecules for novel disrupters of the YAP TEAD interaction. We report the identification of a novel compound (CPD3.1) with the ability to disrupt YAP TEAD protein protein interaction and inhibit TEAD activity, cell proliferation, and cell migration. The YAP TEAD complex is a viable drug target, and CPD3.1 is a lead compound for the development of more potent TEAD inhibitors for treating cancer and other hyperproliferative pathologies.

引用

页码：1291 / 1305

页数：15

共 67 条

[1]

MicroRNA 375 regulates proliferation and migration of colon cancer cells by suppressing the CTGF-EGFR signaling pathway [J].