1. FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice.
Gao, H., Zheng, C., Du, J., Wu, Y., Sun, Y., Han, C., Kee, K. and Rao, Y., 2020. Protein & cell, 11(7), pp.534-539.
Animal models, most commonly mice, that lack a protein of interest play an important role in phenotypic and functional studies of a target gene, allowing researchers to answer various biological questions (Chaible et al., 2010). At present, a variety of tools act at the DNA or RNA level to enable researchers to model gene function (and thus protein) deficiency, including nucleic acid-based RNA interference (Elbashir et al., 2001), antisense oligonucleotides (Schoch and Miller, 2017), and genome editing-based CRISPR-Cas9 (Doudna and Charpentier, 2014) strategies. However, challenges remain. RNA and DNA-based technologies lack exquisite temporal control of the target gene at specified time points in an organism's development, and they fail to realize acute and reversible target gene function (Chan, 2013). These shortcomings have garnered widespread concern in both fundamental research and drug development. Furthermore, gene knockout will often lead to embryonic lethality, precluding the study of post-embryonic pathophysiological functions of target genes and proteins of interest (Dhanjal et al., 2017).
2. Design, synthesis, and evaluation of highly potent FAK-targeting PROTACs.
Gao, H., Wu, Y., Sun, Y., Yang, Y., Zhou, G. and Rao, Y., 2019. ACS medicinal chemistry letters, 11(10), pp.1855-1862.
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.
