Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Mares, Alina; Miah, Afjal H.; Smith, Ian; Rackham, M.D.; Thawani, Aditya R.; Cryan, Jenni; Haile, Pamela A.; Votta, Bartholomew J.; Beal, Allison M.; Capriotti, Carol A.; Reilly, Michael; Fisher, Don T.; Zinn, Nico; Bantscheff, Marcus; MacDonald, Thomas T.; Vossenkämper, Anna; Dace, Phoebe; Churcher, Ian; Benowitz, Andrew B.; Watt, Gillian F.; Denyer, Jane; Scott‐Stevens, Paul; Harling, John D.

doi:10.1038/s42003-020-0868-6

Cited by 160 publications

(146 citation statements)

References 42 publications

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“…Recently, an increasing number of publications have emerged where the physical properties of PROTACs are accounted for in their design, or in the rationalisation of their efficacy [121][122][123][124]. Mares et al [125], developed a potent cIAP-recruiting PROTAC (82) for the degradation of RIPK2 containing a PEG linker (pDC 50 = 9.4 in THP-1 monocytes, Figure 17). However, compound turnover in rat and human microsomes was high (11 and 29 mL/min/g liver respectively) and solubility was poor, which limited its utility as an in vivo tool molecule.…”

Section: Deg S _mentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

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PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design.

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Section: Deg S _mentioning

confidence: 99%

Current strategies for the design of PROTAC linkers: a critical review

Troup

Fallan

Baud

2020

Exploration of Targeted Anti-Tumor Therapy

216

182

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“…Compared with oligonucleotide and CRISPR therapeutics that face in vivo delivery challenges, PROTACs are small molecule therapeutics that provide opportunities to achieve broadly applicable body-wide protein knockdown. Protein degraders have many advantages compared with traditional small molecule inhibitors, including sub-stoichiometric target occupancy 6 , 7 , sustainable pharmacodynamic effects even without constant PROTAC exposure 8 , degradation of the full-length protein to reduce the possibility to develop drug resistance through mutations or compensatory protein overexpression and accumulation 9 , 10 , and enhanced specificity controlled by protein–protein interactions between the targeted protein and the recruited E3 ligase 11 – 14 .…”

Section: Introductionmentioning

confidence: 99%

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

et al. 2020

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Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

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“…Multiple studies are investigating various classes of kinase inhibitors for RIPK1-3 [ 228 ], however given the importance of kinase-dependent cell-death responses to infection, it is critical that we understand the impact of these therapeutic interventions on infection outcomes before introduction to the clinic. The same goes for the recently identified small molecule therapy, Proteolysis-Targeting Chimeras (PROTACs), for the selective degradation of RIPK2 [ 229 ]; given the importance of RIPK2 in detection of multiple intracellular pathogens, what would be the effect on infection outcome?…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The diverse roles of RIP kinases in host-pathogen interactions

Eng

Wemyss

Pearson

2021

Seminars in Cell & Developmental Biology

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Receptor Interacting Protein Kinases (RIPKs) are cellular signaling molecules that are critical for homeostatic signaling in both communicable and non-communicable disease processes. In particular, RIPK1, RIPK2, RIPK3 and RIPK7 have emerged as key mediators of intracellular signal transduction including inflammation, autophagy and programmed cell death, and are thus essential for the early control of many diverse pathogenic organisms. In this review, we discuss the role of each RIPK in host responses to bacterial and viral pathogens, with a focus on studies that have used pathogen infection models rather than artificial stimulation with purified pathogen associated molecular patterns. We also discuss the intricate mechanisms of host evasion by pathogens that specifically target RIPKs for inactivation, and finally, we will touch on the controversial issue of drug development for kinase inhibitors to treat chronic inflammatory and neurological disorders, and the implications this may have on the outcome of pathogen infections.

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Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Cited by 160 publications

References 42 publications

Current strategies for the design of PROTAC linkers: a critical review

Current strategies for the design of PROTAC linkers: a critical review

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry

The diverse roles of RIP kinases in host-pathogen interactions

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