Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

Bemis, Troy A.; Clair, James J. La; Burkart, Michael D.

doi:10.1021/acs.jmedchem.1c00482

Cited by 131 publications

(128 citation statements)

References 71 publications

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“…The application of structural information in models of linker generation is of high relevance for fragment-based drug discovery. While some progress has been made in understanding the role of the linker in compounds designed for targeted protein degradation [8], many aspects remain poorly understood. Supplying enhanced structural information to linker generation methods can lead to better in silico proposals here, allowing to focus in vitro evaluation on more promising candidates.…”

Section: Discussionmentioning

confidence: 99%

“…It is well-known that geometric considerations are crucial for successful linker design in this context. For example, the length of the linker between the two binding fragments plays an important role for a compound's efficacy as a drug [6,7], with linker lengths below some threshold leading to ineffective pharmaceuticals [8]. Accordingly, the linker design process should take into account the desired distance between the fragments.…”

Section: Introductionmentioning

confidence: 99%

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Decoupled coordinates for machine learning-based molecular fragment linking

Fleck¹,

Müller²,

Weber³

et al. 2022

Mach. Learn.: Sci. Technol.

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Recent developments in machine learning-based molecular fragment linking have demonstrated the importance of informing the generation process with structural information specifying the relative orientation of the fragments to be linked. However, such structural information has so far not been provided in the form of a complete relative coordinate system. We present a decoupled coordinate system consisting of bond lengths, bond angles and torsion angles, and show that it is complete. By incorporating this set of coordinates in a linker generation framework, we show that it has a significant impact on the quality of the generated linkers. To elucidate the advantages of such a coordinate system, we investigate the amount of reliable information within the different types of degrees of freedom using both detailed ablation studies and an information-theoretical analysis. The presented benefits suggest the application of a complete and decoupled relative coordinate system as a standard good practice in linker design.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decoupled coordinates for machine learning-based molecular fragment linking

Fleck¹,

Müller²,

Weber³

et al. 2022

Mach. Learn.: Sci. Technol.

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“…The linker length and composition are crucial parameters for a successful design of an effective PROTACs. A linker may provide the best chances of selectivity by minimizing degrees of freedom in the ternary complex while maintaining effectiveness (Bemis, Clair, and Burkart 2021). Other limitations of current PROTACS are based on both the selected POI and the targeted tumour type.…”

Section: Advantages and Disadvantages Of Protacs Technologymentioning

confidence: 99%

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Juan¹,

Noblejas-López

Arenas-Moreira³

et al. 2022

Front. Cell Dev. Biol.

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Classical targeting in cancer focuses on the development of chemical structures able to bind to protein pockets with enzymatic activity. Some of these molecules are designed to bind the ATP side of the kinase domain avoiding protein activation and the subsequent oncogenic activity. A further improvement of these agents relies on the generation of non-allosteric inhibitors that once bound are able to limit the kinase function by producing a conformational change at the protein and, therefore, augmenting the antitumoural potency. Unfortunately, not all oncogenic proteins have enzymatic activity and cannot be chemically targeted with these types of molecular entities. Very recently, exploiting the protein degradation pathway through the ubiquitination and subsequent proteasomal degradation of key target proteins has gained momentum. With this approach, non-enzymatic proteins such as Transcription Factors can be degraded. In this regard, we provide an overview of current applications of the PROteolysis TArgeting Chimeras (PROTACs) compounds for the treatment of solid tumours and ways to overcome their limitations for clinical development. Among the different constraints for their development, improvements in bioavailability and safety, due to an optimized delivery, seem to be relevant. In this context, it is anticipated that those targeting pan-essential genes will have a narrow therapeutic index. In this article, we review the advantages and disadvantages of the potential use of drug delivery systems to improve the activity and safety of PROTACs.

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“…4). [42][43] Briefly, taking 7A3-MN7-17B3 as an example, the starting orientations of the 7A3-MEL and 17B3-NIA binding moieties should be first provided to form an initial configuration. After 7A3 and 17B3 protein-protein docking to determine the relative position of the two mAbs, the 7A3-MEL and 17B3-NIA binding moieties were superimposed onto their respective mAbs in the 7A3-17B3 complex to form a shared binding cavity.…”

Section: Molecular Recognition Mechanism By Molecular Docking and Mol...mentioning

confidence: 99%

Minimum Distance Between Two Epitopes in Sandwich Immunoassays for Small Molecules

Bai

Fei

et al. 2022

Preprint

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The pursuit of the limit between dimensionalities is a scientific goal with high applicability. Sandwich immunoassay, usually based on two antibodies binding two epitopes, is one of the most popular mainstay tools in both academic and industrial fields. Herein, we determined and evaluated the minimum distance of two epitopes in sandwich immunoassays for small molecules. Briefly, nine model analytes comprising two hapten epitopes, i.e., melamine (MEL) and p-nitroaniline (NIA), were designed by increasing the linear chain linkers brick by brick. Two groups of monoclonal antibodies (mAbs) were produced with different recognition properties toward MEL and NIA using 12 new haptens with different spacer arms. The results indicated that two epitopes of the analyte with a distance of only 2.4 Å could be simultaneously bound by two mAbs, which is the known limit of epitope distance in sandwich immunoassays thus far. We further found that an epitope distance of below 8.8 Å for the analyte generally induces noticeable steric hindrance of antibodies, preventing a sandwich immunoassay with high probability. These observations were investigated and evaluated by molecular docking, molecular dynamics, and surface plasmon resonance and using model and real analytes. Altogether, we determined the minimum distance of two epitopes and explored the molecular mechanism of the antibody–analyte–antibody ternary complex in sandwich immunoassays, providing a theoretical basis for hapten design, antibody discovery and development, and sandwich immunoassay establishment for small molecules.

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Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

Cited by 131 publications

References 71 publications

Decoupled coordinates for machine learning-based molecular fragment linking

Decoupled coordinates for machine learning-based molecular fragment linking

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Minimum Distance Between Two Epitopes in Sandwich Immunoassays for Small Molecules

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