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Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs.

ABSTRACT: Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that allow direct post-translational knockdown of proteins via ubiquitination of a target protein by E3 ubiquitin ligase and subsequent proteasomal degradation. Here, we designed and synthesized a FAK PROTAC library with FAK inhibitor (PF562271 or VS6063) and CRBN E3 ligand. A novel FAK-targeting PROTAC, FC-11, showed a rapid and reversible FAK degradation with a picomolar of DC₅₀ in various cell lines in vitro, which imply that FAK-PROTACs could be useful as expand tools for studying functions of FAK in biological system and as potential therapeutic agents.

SUBMITTER: Gao H

PROVIDER: S-EPMC7549110 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs.

Gao Hongying H Wu Yue Y Sun Yonghui Y Yang Yiqing Y Zhou Guangbiao G Rao Yu Y

ACS medicinal chemistry letters 20191022 10

Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that allow direct post-translational knockdown of proteins via ubiquitination of a target prot ...[more]

PMID: 33062164

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