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2025 , 147 , 25 , 21512–21525 [link] Targetedproteindegradation (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.
In Wednesday’s Flash Talk webinar , we covered recent highlights in targetedproteindegradation, with lots of great questions from the audience. KT-333 and KT-003) AR degraders and ER degraders from Arvinas (bavdegalutamide/ARV-110, ARV-766, and ARV-471) MDM2 degraders from Kymera (e.g.
Nomura ACS Chemical Biology 2024 DOI: [link] Targetedproteindegradation with proteolysis targeting chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation. Huang, Ingrid E.
Seong Ho Hong , Akane Osa , Ingrid E Wertz , Daniel Nomura bioRxiv 2023.10.20.563371; doi: [link] Targetedproteindegradation with Proteolysis Targeting Chimeras (PROTACs) is a powerful therapeutic modality for eliminating disease-causing proteins through targeted ubiquitination and proteasome-mediated degradation.
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 targetedproteindegradation (TPD).
link] Targetedproteindegradation (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.
Calabrese Nat Commun 14 , 1189, 2023 [link] Targetedproteindegradation using heterobifunctional chimeras holds the potential to expand target space and grow the druggable proteome. Bridging covalent ligand discovery with chimeric degrader design has emerged as a potential mechanism to advance both fields.
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.
Expanding TargetedProteinDegradation in Hematologic Malignancies Targetedproteindegradation is a powerful therapeutic approach designed to destroy disease-driving proteins within cells, thereby inhibiting their ability to contribute to disease progression.
Targetedproteindegradation has emerged as one of the more competitive areas of pharmaceutical research in recent years as scientists develop new ways to reach difficult-to-drug targets.
Scientists generate new targetedproteindegradation system that tunes a cell’s own proteins By Leah Eisenstadt March 14, 2024 Breadcrumb Home Scientists generate new targetedproteindegradation system that tunes a cell’s own proteins Researchers have engineered a compact degron tag that can be precisely edited into a cell’s genome, enabling scientists (..)
Unlike traditional drug discovery, which focuses on inhibiting or activating proteins, TPD offers a more precise and efficient way to alter cellular pathways. 1 The concept of TPD was first demonstrated with a heterobifunctional small molecule to degrader a protein of interest in the early 2000s. How does TPD work? Nature News.
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 targetedproteindegradation.
Winter, Bioorganic & Medicinal Chemistry Letters , 2024 [link] Targetedproteindegradation is mediated by small molecules that induce or stabilize protein–protein interactions between targets and the ubiquitin–proteasome machinery. Gary Tin, Marko Cigler, Matthias Hinterndorfer, Kevin D. Gygi, Georg E.
The alliance, which aims to combine Seagen’s antibody expertise with Nurix’s targetedproteindegradation research, comes as the larger biotech awaits its acquisition by Pfizer to close.
Ashley R Julio, Flowreen Shikwana, Cindy Truong, Nikolas R Burton, Emil Dominguez, Alexandra Turmon, Jian Cao, Keriann Backus bioRxiv 2023.10.30.564067; doi: [link] Protein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways.
link] Targetedproteindegradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to targetproteins for proteasomal degradation. Tabor, J.R., Nat Chem Biol (2024).
The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targetedproteindegradation.
This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targetedproteindegradation therapies.
The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targetedproteindegradation.
This article highlights six recent articles of interest in the field of targetedproteindegradation including but not limited to potentially new ligases, recruiting motifs, and a discussion on the feasibility of CNS-penetrant degraders.
Ebert, Nathanael Gray bioRxiv 2023 [link] Small molecules that can induce proteindegradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand the number of proteins that can be manipulated pharmacologically.
3c06622 Targetedproteindegradation relies on small molecules that induce new protein–protein interactions between targets and the cellular proteindegradation machinery. Chouchani, Mikołaj Słabicki, Eric S. Fischer, Benjamin L. Ebert, Stephen M. Hinshaw, and Nathanael S.
Sygnature Discovery, the global integrated drug discovery company, has unveiled a new platform that facilitates the combinational high-throughput assembly and review of molecular degraders ( CHARMED ), in response to a sustained rise in demand for its multi-disciplinary expertise. What is the CHARMED platform?
Property Prediction Machine Learning Methods for Small Data Challenges in Molecular Science [link] Practical guidelines for the use of gradient boosting for molecular property prediction [link] Application of message passing neural networks for molecular property prediction [link] Molecular Similarity Molecular Similarity: Theory, Applications, and (..)
Gray bioRxiv 2024.09.25.615094; doi: [link] Targeted covalent inhibition (TCI) and targetedproteindegradation (TPD) have proven effective in pharmacologically addressing formerly ‘undruggable’ targets. Nix, Jianing Zhong, Mikołaj Słabicki, Eric S. Fischer, Benjamin L. Ebert, Nathanael S.
We therefore set out to understand the nonenzymatic functions of BTK and explored targetedproteindegradation to overcome the oncogenic scaffold function of mutant BTK. In this study, we found that a group of these mutants impair BTK kinase activity despite still enabling downstream BCR signaling.
Evotec and Bristol Myers Squibb (the successor in interest to Celgene ) initiated their long-term strategic drug discovery and development partnership in the field of targetedproteindegradation in 2018 with the goal to identify novel drug targets.
In person Molecular glues and targetedproteindegraders are revolutionizing the field of drug discovery, offering promising solutions for a range of diseases, including cancer, infectious, inflammatory, and neurodegenerative diseases. The recent emergence of the molecular glue class of proteindegraders is paving.
This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targetedproteindegradation researchers, and brain-penetrant HER2 and ROCK2 inhibitors.
Proteindegradation in the cell Research over many years helped build a comprehensive picture of protein synthesis in the cell. However, knowledge of how proteins are broken down and how degradation contributes to cellular regulation is more recent.
Options for cell-based proteindegrader assays Interest is growing in the use of targeted-proteindegradation to induce the breakdown of disease-causing proteins after treatment with small molecule drugs.
Sygnature Discovery identifies potent SHP2 degrader compounds using its proprietary targetedproteindegrader platform, CHARMED, in collaboration with Japanese specialty chemical company, UBE Corporation.
Hypha’s Q3 2024 Newsletter – Metabolism of degraders, gut metabolites, qNMR and more Focus topics for this edition: Metabolism of targetedproteindegraders drugs such as PROTACs. Novel fecal metabolites of inavolisib (GDC-0077). The role of NMR spectroscopy in drug metabolism studies.
In person Molecular glues and targetedproteindegraders are revolutionizing the field of drug discovery, offering promising solutions for a range of diseases, including cancer, infectious, inflammatory, and neurodegenerative diseases. The recent emergence of the molecular glue class of proteindegraders is paving.
I consider it essential to account for numbers of adjustable parameters and for correlations between descriptors (or features if you prefer) when building QSAR-like ML models, and I’m also concerned that the challenges presented by clustering in descriptor spaces are not properly acknowledged.
Past Speakers Speaker Topic Casey Krusemark Encoding chemicals and assays with DNA: Applications in Medicinal Chemistry and Biology Morgan Sheng Schizophrenia and bipolar disorder: from human genetics towards mechanisms and therapeutics Malvina Papanastasiou Structural insights into the LSD1 N-terminus using hydrogen/deuterium exchange-mass spectrometry (..)
In person Molecular glues and targetedproteindegraders are changing the landscape of drug discovery. They show great potential for treating diseases such as cancer, infectious, inflammatory, andneurodegenerative diseases, especially for those with “undruggable” pathogenic proteintargets.
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