Targeted protein degradation in vivo with Proteolysis Targeting Chimeras: Current status and future considerations

Watt, Gillian F.; Scott‐Stevens, Paul; Gaohua, Lu

doi:10.1016/j.ddtec.2019.02.005

Cited by 62 publications

(47 citation statements)

References 43 publications

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“…14,15,19,20 The eld of proteolysis targeting chimeras (PROTACs) has made tremendous achievements and reached substantial milestones in the last years. [21][22][23][24][25][26][27][28][29] Briey, PROTACs are bifunctional small molecules, which comprise two linker-connected moieties that simultaneously bind a target protein and an E3 ubiquitin ligase. Frequently employed E3 ligase binders 3-6 which have successfully been utilized in PROTAC design are presented in Fig.…”

Section: Introductionmentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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“…In these cases, PROTACs may enable a disconnect between pharmacokinetics (PK) and pharmacodynamics (PD) to provide extended duration of in vivo efficacy long after the PROTAC has been cleared from systemic circulation. This PK/PD disconnect may provide novel opportunities to develop medicines with low human doses and infrequent dosing regimens, although to date this potential has only been anticipated 13 with no rigorous preclinical in vivo data available to support this hypothesis to our knowledge.…”

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confidence: 99%

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

et al. 2020

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Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

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“…The use of proteolysis targeting chimeras (PROTACs) for induction of specific protein degradation has emerged as promising approach for targeting proteins that are otherwise hard or impossible to target by small molecule approaches (Watt et al, 2019), making further research of the Ub system a priority. Still, there are many things that we do not know or that we have just started to elucidate.…”

Section: Discussionmentioning

confidence: 99%

Resolving the Complexity of Ubiquitin Networks

Kliza

Husnjak

2020

Front. Mol. Biosci.

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Ubiquitination regulates nearly all cellular processes by coordinated activity of ubiquitin writers (E1, E2, and E3 enzymes), erasers (deubiquitinating enzymes) and readers (proteins that recognize ubiquitinated proteins by their ubiquitin-binding domains). By differentially modifying cellular proteome and by recognizing these ubiquitin modifications, ubiquitination machinery tightly regulates execution of specific cellular events in space and time. Dynamic and complex ubiquitin architecture, ranging from monoubiquitination, multiple monoubiquitination, eight different modes of homotypic and numerous types of heterogeneous polyubiquitin linkages, enables highly dynamic and complex regulation of cellular processes. We discuss available tools and approaches to study ubiquitin networks, including methods for the identification and quantification of ubiquitin-modified substrates, as well as approaches to quantify the length, abundance, linkage type and architecture of different ubiquitin chains. Furthermore, we also summarize the available approaches for the discovery of novel ubiquitin readers and ubiquitin-binding domains, as well as approaches to monitor and visualize activity of ubiquitin conjugation and deconjugation machineries. We also discuss benefits, drawbacks and limitations of available techniques, as well as what is still needed for detailed spatiotemporal dissection of cellular ubiquitination networks.

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Targeted protein degradation in vivo with Proteolysis Targeting Chimeras: Current status and future considerations

Cited by 62 publications

References 43 publications

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

Resolving the Complexity of Ubiquitin Networks

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