Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras

Xia, Liwen; Ba, Mengyu; Liu, Wei; Cheng, Weyland; Hu, Chao-Ping; Zhao, Qingjie; Yao, Yongfang; Sun, Moran; Duan, Yongtao

doi:10.4155/fmc-2019-0159

Cited by 39 publications

(21 citation statements)

References 101 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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“…A significant number of reported PROTACs incorporate a triazole fragment (e.g., compound 13 , Scheme 3 ; compound 34 , Scheme 7 ; compound 39 , Scheme 8 ) as a result of utilizing click reactions between azides and alkynes (e.g., compound 12 in Scheme 3 ), under conditions for a typical copper-catalyzed Huisgen 1,3-dipolar cycloaddition. Deemed the ‘privileged scaffold for PROTACs’, triazoles represent numerous advantages since they are easily accessible in high yields under mild reaction conditions, which are highly compatible with other functional groups ( Xia et al, 2019 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

et al. 2021

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Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

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“…One of the most common strategies to combine TOI and ligase binder is the use of click chemistry (Wurz et al, 2018), a copper-catalyzed reaction that consists of a Huisgen 1,3-dipolar cycloaddition, which involves an azide and an alkyne moiety. Besides the wide applicability and high compatibility of this linking strategy, the resulting triazole ring may also represent a metabolic advantage compared to linear linkers, which are more easily exposed to oxidative metabolism in vivo (Xia et al, 2019).…”

Section: Challenges In Expanding the E3 Ligase Toolbox In Targeted Protein Degradationmentioning

confidence: 99%

“…As expected, this modification led to improved pharmacokinetic profiles and thus good activity in vivo for BTK degraders (Jaime-Figueroa et al, 2020). The presence of a triazole in the linker seems to be another element to address the issues related to metabolic oxidation in vivo (Xia et al, 2019).…”

Section: In Vivo Efficacy Of Protacsmentioning

confidence: 99%

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

et al. 2021

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Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). This modality has emerged as an orthogonal approach to the use of small-molecule inhibitors for knocking down classic targets and disease-related proteins classified, until now, as “undruggable.” In early 2019, the first targeted protein degraders reached the clinic, drawing attention to PROTACs as one of the most appealing technology in the drug discovery landscape. Despite these promising results, PROTACs are often affected by poor cellular permeability due to their high molecular weight (MW) and large exposed polar surface area (PSA). Herein, we report a comprehensive record of PROTAC design, pharmacology and thermodynamic challenges and solutions, as well as some of the available strategies to enhance cellular uptake, including suggestions of promising biological tools for the in vitro evaluation of PROTACs permeability toward successful protein degradation.

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Triazol: A Privileged Scaffold for Proteolysis Targeting Chimeras

Cited by 39 publications

References 101 publications

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

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

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation

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