4 results match your criteria: "Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu.[Affiliation]"
Targeted covalent inhibitors possess advantages over reversible binding drugs, that include higher potency, enhanced selectivity and prolonged pharmacodynamic duration. The standard paradigm for covalent inhibitor discovery relies on the use of α,β-unsaturated carbonyl electrophiles to engage the nucleophilic cysteine thiol, but due to its rarity in binding sites, the amino acid is often not available for targeting. 10 years ago we highlighted the emerging potential of sulfonyl fluoride chemical probes that were initially found to serendipitously modify residues beyond cysteine, including tyrosine, lysine, histidine, serine and threonine.
View Article and Find Full Text PDFDevelopment of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.
RSC Med Chem
February 2024
Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA
Article Synopsis
- Sulfonyl fluoride EM12-SF was previously designed to target a specific histidine in cereblon (CRBN), part of a complex that regulates protein degradation.* -
- The study discovered that isoindoline EM364-SF, despite missing a crucial bonding feature, effectively binds to CRBN and led to the creation of a reversible molecular glue, CPD-2743.* -
- CPD-2743 demonstrated strong cell-based binding to CRBN, effectively degrading the neosubstrate IKZF1 without causing teratogenic side effects, showcasing advancements in chemical biology and medicinal chemistry design.*
Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead.
RSC Chem Biol
November 2023
Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA
Many cereblon (CRBN) ligands have been used to develop proteolysis targeting chimeras (PROTACs), but all are reversible binders of the E3 ubiquitin ligase. We recently described the use of sulfonyl exchange chemistry to design binders that covalently engage histidine 353 in CRBN for the first time. Here we show that covalent CRBN ligands can be used to develop efficient PROTAC degraders.
View Article and Find Full Text PDFCereblon covalent modulation through structure-based design of histidine targeting chemical probes.
RSC Chem Biol
August 2022
Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA
Article Synopsis
- - The study focuses on creating new covalent inhibitor drugs by targeting histidine residues in proteins, as traditional methods often rely on targeting cysteine, which is less common in binding sites.
- - The researchers utilized structure-based drug design to develop the compound EM12, which effectively interacts with a specific histidine (His353) in the cereblon E3 ubiquitin ligase complex, leading to potent inhibition.
- - Additionally, the compound EM12-FS, while able to label His353, also disrupts a related protein essential for certain cellular processes, showcasing the potential for targeted protein degradation in drug discovery.