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Covalent Recruitment of NEDD4 for Targeted Protein Degradation: Rational Design of Small Molecular Degraders

Covalent Modifiers

2025 , 147 , 25 , 21512–21525 [link] Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy for treating various diseases. However, current small molecule degraders predominantly rely on a limited set of E3 ubiquitin ligases, such as CRBN and VHL, which restricts their applications.

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Covalency in PROTACs: Mechanisms and applications [@RPNowak]

Covalent Modifiers

Nowak Annual Reports in Medicinal Chemistry , 2024 [link] Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that remove disease-causing proteins through the means of targeted protein degradation (TPD).

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Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders

Covalent Modifiers

link] Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. 2025 , e202508427.

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Bristol Myers Squibb Highlights Targeted Protein Degradation Data, Including CELMoD Agents, at EHA 2025

The Pharma Data

Expanding Targeted Protein Degradation in Hematologic Malignancies Targeted protein degradation is a powerful therapeutic approach designed to destroy disease-driving proteins within cells, thereby inhibiting their ability to contribute to disease progression.

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The Roles of Degrons in Targeted Protein Degradation | BMG LABTECH

BMG Labtech

At the most fundamental level you can think of a degron as a sequence of amino acids or a structural motif that can facilitate the degradation of protein substrates.

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N-Acyl-N-alkyl/aryl Sulfonamide Chemistry Assisted by Proximity for Modification and Covalent Inhibition of Endogenous Proteins in Living Systems

Covalent Modifiers

Second, we highlight various recent examples of protein functionalization using NASA/ArNASA chemistry, such as visualization of membrane proteins including therapeutically important G-protein coupled receptors, gel-based ligand screening assays, photochemical control of protein activity, and targeted protein degradation.

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The future of CNS drug development: signs of real progress

Drug Target Review

PROTACs are larger than traditional small-molecule inhibitors, so challenges arise in permeating the BBB, but they can target proteins previously considered ‘undruggable’. Targeted protein degraders can easily cause off-target toxicity.