期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 140, 期 49, 页码 17019-17026出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b08008
关键词
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资金
- Alexander von Humboldt Foundation
- National Cancer Institute specialist award [R50CA211252]
- U.S. National Institutes of Health [R35CA197589]
Enzymatic inhibition has proven to be a successful modality for the development of many small-molecule drugs. In recent years, small-molecule-induced protein degradation has emerged as an orthogonal therapeutic strategy that has the potential to expand the druggable target space. Focal adhesion kinase (Fak) is a key player in tumor invasion and metastasis, acting simultaneously as a kinase and a scaffold for several signaling proteins. While previous efforts to modulate Fak activity were limited to kinase inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously block Fak's kinase signaling and scaffolding capabilities. Here, we report the development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect to Fak activation as well as Fak-mediated cell migration and invasion. These results underline the potential that PROTACs offer in expanding the druggable space and controlling protein functions that are not easily addressed by traditional small-molecule therapeutics.
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