Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Popow, Johannes; Arnhof, Heribert; Bader, Gerd; Berger, Helmut; Ciulli, Alessio; Covini, David; Dank, Christian; Gmaschitz, Teresa; Greb, Peter; Karolyi-Özguer, Jale; Koegl, Manfred; McConnell, Darryl B.; Pearson, Mark; Rieger, Maria; Rinnenthal, Joerg; Roessler, Vanessa; Schrenk, Andreas; Spina, Markus; Steurer, Steffen; Trainor, Nicole; Traxler, Elisabeth; Wieshofer, Corinna; Zoephel, Andreas; Ettmayer, Peter

doi:10.1021/acs.jmedchem.8b01826

Cited by 116 publications

(101 citation statements)

References 52 publications

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“…FC-11 (PF562271-based FAK PROTAC) showed picomolar FAK degradation in the tested cell lines (the DC 50 in the tested cell lines were 40 pM in Ramos, 80 pM in PA1, 310 pM in TM3, 330 pM in MDA-MB-436 and 370 pM in LNCaP cell lines). However, like the other reported FAK PROTACs, 100,243 FC-11 did not affect the cell proliferation in the tested cell lines to a greater extent than PF562271. Therefore, more work is required to study FAK-related biology.…”

Section: Faksupporting

confidence: 64%

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PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

438

414

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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Section: Faksupporting

confidence: 64%

“…Compound 44 showed better protein selectivity and potent protein degradation. Its DC 50 In 2019, the Peter Ettmayer group developed two highly selective and functional FAK-targeting PROTACs (BI-3663 and BI-0319) by utilizing both CRBN and VHL ligands 243 (Fig. 26).…”

Section: Fakmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

438

414

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“…1 ) [ 17 , 18 ]. In mammalian cells there are two E1 that can bind to forty E2s, which can bind with hundreds of E3s in a hierarchical way [ 19 ]. In the activation process, E1 enzymes bind both ATP and ubiquitin and catalyse the acyl-adenylation of the C-terminus of the ubiquitin molecule and transfer ubiquitin to a cysteine residue producing a thioester linkage between the C-terminal carboxyl group of ubiquitin and the sulfhydryl group of the E1 cysteine [ 17 , 18 ].…”

Section: Protein Degradation and The Ubiquitination Systemmentioning

confidence: 99%

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Ocaña

Pandiella

2020

J Exp Clin Cancer Res

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Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting.

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“…To maximize the chance of finding the non-kinase targets of sorafenib, we coupled the linker with the N-methylpicolinamide group of sorafenib, and we hope that the linker added to the N-methylpicolinamide group would reduce the kinase binding activity. Since 3-polyethylene glycol (PEG) linkers were widely used in the literature for CRBN-recruiting PROTACs 15,20,21 , we coupled sorafenib with a 3-PEG linker conjugated to thalidomide (referred to PROTAC T-S) ( Figure 1A). We then tested the kinase binding activity of PROTAC T-S by using known kinase targets of sorafenib, including BRAF, c-KIT, FLT3, P38α, VEGFR2 and PDGFRβ.…”

Section: Design Of Sorafenib-based Protac (Protac T-s)mentioning

confidence: 99%

Identification of PDE6D as a potential target of sorafenib via PROTAC technology

Yang

Meng

Wang

et al. 2020

Preprint

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These authors contributed equally to this work. AbstractThe identification of unknown target of a multi-kinase inhibitor sorafenib is important to better understand the mechanism of action of this drug in anti-cancer and anti-fibrotic treatments. Here, we report the combination of PROTAC technique with quantitative proteomic analysis to identify the unknown cellular targets of sorafenib. Sorafenib-based PROTAC can strongly degrade a non-kinase target PDEδ in different types of cells.We also confirmed the direct binding interaction of PDEδ with sorafenib by CETSA and SPR assays. Together, our research suggests that PDEδ is a new potential target of sorafenib, and PROTAC technology may be a promising approach for cellular target identification of bioactive compounds of interest. KEY WORDS PDE6D;PROTAC; Protein degradation;Ubiquitylation; Target identificationHere, we report the design and synthesis of a sorafenib-based PROTAC T-S. Upon the recruitment of Cereblon (CRBN)/Cullin 4A E3 ligase complex, we identified the prenyl-binding protein PDEδ as a dominant target of sorafenib-based PROTAC T-S. Furthermore, we verified the direct binding interaction between sorafenib and PDEδ. These data gave us a new insight into the mechanism of action of sorafenib.

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Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Cited by 116 publications

References 52 publications

PROTACs: great opportunities for academia and industry

PROTACs: great opportunities for academia and industry

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Identification of PDE6D as a potential target of sorafenib via PROTAC technology

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