HaloTag‐Targeted Sirtuin‐Rearranging Ligand (SirReal) for the Development of Proteolysis‐Targeting Chimeras (PROTACs) against the Lysine Deacetylase Sirtuin 2 (Sirt2)**

Schiedel, Matthias; Lehotzky, Attila; Szunyogh, Sándor; Oláh, Judit; Hammelmann, Sören; Wössner, Nathalie; Robaa, Dina; Einsle, Oliver; Sippl, Wolfgang; Ovádi, Judit; Jung, Manfred

doi:10.1002/cbic.202000351

Cited by 21 publications

(14 citation statements)

References 51 publications

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“…On the other hand, parkin E3 ligase exhibited moderate efficiency but showed broad responsiveness to all HaloPROTACs tested. Such HaloTag fusion proteins have also been utilized to develop Sirtuin-targeted PROTACs (termed SirReal, Figure 6 ) [ 92 ]. Quantitative analysis revealed distinct concentration-dependent effects on these HaloTag-E3 ligases of interest.…”

Section: Halotag-assisted Targeted Protein Modificationsmentioning

confidence: 99%

Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond

Lawer,

Schulz,

Sawyer

et al. 2024

Cells

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Post-translational modifications (PTMs) are crucial mechanisms that underlie the intricacies of biological systems and disease mechanisms. This review focuses on the latest advancements in the design of heterobifunctional small molecules that hijack PTM machineries for target-specific modifications in living systems. A key innovation in this field is the development of proteolysis-targeting chimeras (PROTACs), which promote the ubiquitination of target proteins for proteasomal degradation. The past decade has seen several adaptations of the PROTAC concept to facilitate targeted (de)phosphorylation and acetylation. Protein fusion tags have been particularly vital in these proof-of-concept studies, aiding in the investigation of the functional roles of post-translationally modified proteins linked to diseases. This overview delves into protein-tagging strategies that enable the targeted modulation of ubiquitination, phosphorylation, and acetylation, emphasizing the synergies and challenges of integrating heterobifunctional molecules with protein tags in PTM research. Despite significant progress, many PTMs remain to be explored, and protein tag-assisted PTM-inducing chimeras will continue to play an important role in understanding the fundamental roles of protein PTMs and in exploring the therapeutic potential of manipulating protein modifications, particularly for targets not yet addressed by existing drugs.

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Section: Halotag-assisted Targeted Protein Modificationsmentioning

confidence: 99%

Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond

Lawer,

Schulz,

Sawyer

et al. 2024

Cells

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“…In 2018, a sirtuin rearrangement ligand (SirReals), as a highly potent and isoform-selective Sirt2 inhibitor conjugated to thalidomide, a bona fide cerebellar ligand, a PROTAC was developed to induce the degradation of Sirt2 in HeLa (Cervical cancer) cells and inhibit cell viability. On this basis, the team developed a PROTAC that used Parkin as an E3 ubiquitin ligase to target SIRT2 for degradation, providing a new direction for the development of PROTACs [ 88 , 89 ]. Subsequently, two PROTACs, TM-P2-Thal and TM-P4-Thal, were produced.…”

Section: Protacs For Epigenetic Targets In Cancermentioning

confidence: 99%

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

et al. 2023

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The epigenetic regulation of gene functions has been proven to be strongly associated with the development and progression of cancer. Reprogramming the cancer epigenome landscape is one of the most promising target therapies in both treatments and in reversing drug resistance. Proteolytic targeted chimeras (PROTACs) are an emerging therapeutic modality for selective degradation via the native ubiquitin-proteasome system. Rapid advances in PROTACs have facilitated the exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. A lot of PROTAC degraders have already been designed in the field of epigenetic cancer therapy, and PROTACs targeting epigenetic proteins can better exploit target druggability and improve the mechanistic understanding of the epigenetic regulation of cancer. Thus, this review focuses on the progress made in the development of PROTAC degraders and PROTAC drugs targeting epigenetics in cancer and discusses challenges and future opportunities for the field.

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“…The results showed that PROTAC 54 can selectively and dose-dependently degrade sirt2 compared with Sirt2 inhibition. Subsequently, they designed and developed a Sirt2 degrader PROTAC 55 ( Table 2 ) [ 159 ] with a more optimized performance compared with PROTAC 54. PROTAC 55 can degrade Sirt2 at a 10-fold lower concentration than PROTAC 54.…”

Section: Application Of Protac In Immune Diseasesmentioning

confidence: 99%

Recent Advances in PROTACs for Drug Targeted Protein Research

Yao

Xiao

Wang

et al. 2022

IJMS

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Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell. At present, PROTAC, as a new type of drug, has been developed to degrade a variety of cancer target proteins and other disease target proteins, and has shown good curative effects on a variety of diseases. For example, PROTACs targeting AR, BR, BTK, Tau, IRAK4, and other proteins have shown unprecedented clinical efficacy in cancers, neurodegenerative diseases, inflammations, and other fields. Recently, PROTAC has entered a phase of rapid development, opening a new field for biomedical research and development. This paper reviews the various fields of targeted protein degradation by PROTAC in recent years and summarizes and prospects the hot targets and indications of PROTAC.

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HaloTag‐Targeted Sirtuin‐Rearranging Ligand (SirReal) for the Development of Proteolysis‐Targeting Chimeras (PROTACs) against the Lysine Deacetylase Sirtuin 2 (Sirt2)**

Cited by 21 publications

References 51 publications

Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond

Harmony of Protein Tags and Chimeric Molecules Empowers Targeted Protein Ubiquitination and Beyond

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

Recent Advances in PROTACs for Drug Targeted Protein Research

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