Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs

Law, Robert P.; Nunes, João; Chung, Chun‐wa; Bantscheff, Marcus; Buda, Karol; Han, Dongmei; Evans, John P.; Flinders, Adam; Klimaszewska, Diana; Lewis, Antonia J.; Muelbaier, Marcel; Scott‐Stevens, Paul; Stacey, Peter; Tame, Christopher J.; Watt, Gillian F.; Zinn, Nico; Queisser, Markus A.; Harling, John D.; Benowitz, Andrew B.

doi:10.1002/anie.202109237

Cited by 84 publications

(80 citation statements)

References 39 publications

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“…The last structure we cover is of a CRL2 VHL -recruiting PROTAC degrader of focal adhesion kinase (FAK, also known as PTK2) (120), an important cancer target in solid tumours that is associated with poor clinical outcomes (121,122). FAK-degrading PROTACs active in cellular assays had previously been reported by groups at Yale University (CRL2 VHL -recruiting), Boehringer Ingelheim/University of Dundee (CRL2 VHL -or CRL4 CRBN -recruiting), and Tsinghua University (CRL4 CRBN -recruiting) (123)(124)(125).…”

Section: Protacsmentioning

confidence: 99%

“…FAK-degrading PROTACs active in cellular assays had previously been reported by groups at Yale University (CRL2 VHL -recruiting), Boehringer Ingelheim/University of Dundee (CRL2 VHL -or CRL4 CRBN -recruiting), and Tsinghua University (CRL4 CRBN -recruiting) (123)(124)(125). Although some have since been shown to be active in mouse models (126)(127)(128), biophysical characterisation of ternary complex formation and structure were lacking prior to work by Law et al (120). In this study, PROTACs were designed based on the FAK inhibitor VS-4718/PND-1186 (129) and the VHL ligand (130) with different linkers.…”

Section: Protacsmentioning

confidence: 99%

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Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory

Cowan

Ciulli

2022

Annu. Rev. Biochem.

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Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin–proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein–protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Protacsmentioning

confidence: 99%

Section: Protacsmentioning

confidence: 99%

Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory

Cowan

Ciulli

2022

Annu. Rev. Biochem.

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“…In detail, this PROTAC molecule in mouse liver was able to degrade FAK at low doses and in a rapid and prolonged manner. This study should be useful for the study of FAK-degradation biology in vivo, confirming that FAK-PROTACs could be potential therapeutic agents to treat FAK-related diseases [ 68 ].…”

Section: Protac Moleculesmentioning

confidence: 65%

The Development of FAK Inhibitors: A Five-Year Update

Spallarossa

Tasso

Russo

et al. 2022

IJMS

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

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“…22 ) based on VS-4718 and VHL ligand. 159 Interestingly, it was confirmed that degrader 95 ( GSK-215 ) which possessed a short and rigid linker generated a highly cooperative ternary complex by SPR and X-ray crystallography data. It induced the degradation of FAK with DC 50 of 1.3 nM in A549 cells and induced cell proliferation inhibition in A549, MCF-7 cells rather than BT474 cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 89%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

135

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs

Cited by 84 publications

References 39 publications

Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory

Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory

The Development of FAK Inhibitors: A Five-Year Update

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

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