Last paper post of the year!
Amazing Nature Chemical Biology paper by the group of Christina Woo. PCMT1 installs cyclic imides on asparagines at the C-terminus of proteins via SAM-dependent methyl ester formation, which then leads to degradation using cereblon.
https://www.nature.com/articles/s41589-025-02106-9
#Chemistry #ChemBio #TPD #TargetedProteinDegradation #Degraders
The enzyme PCMT1 was found to install a C-terminal cyclic imide modification on proteins that marks them for degradation by CRBN, uncovering a conserved protein turnover pathway with implications in metabolism and neurological function.
Superannuation funds accused of delaying disability insurance claims
William Johns is deeply frustrated by the way some of Australia’s major superannuation funds are treating their members.…
#NewsBeep #News #Headlines #ASFA #AU #Australia #disbailityclaims #insurance #insuranceclaims #mentalhealthclaims #mentalheath #super #superconsumersaustralia #superfunds #superannuation #totalandpermanentdisability #tpd
https://www.newsbeep.com/310052/
Exciting study by the group of Alexander Adibekian in JACS. They used antibodies modified with reversible, lysine-directed ketoboronates to develop KB-TACs as lysosomal degraders of membrane and extracellular proteins.
https://doi.org/10.1021/jacs.5c16611
#Chemistry #ChemBio #ChemicalProteomics #DrugDiscovery #TPD
Extracellular and membrane-associated proteins play essential roles in nearly all our body’s biochemical processes and are implicated in cancer, autoimmune disorders, and neurodegenerative diseases. Consequently, a selective and universally applicable technique for the degradation of these proteins in disease-relevant conditions could significantly improve human health prospects. Lysosome-targeting chimeras (LYTACs) are bifunctional degraders comprising of an antibody conjugated with a cell–surface receptor ligand that enables cargo lysosome shuttling and degradation. Herein, we demonstrate that conjugation of antibodies with a small ketoboronate-based, lysine-reactive, covalent-reversible uptake tag (KB) enables the internalization of plasma membrane and extracellular proteins, directing them to lysosomal degradation via receptor-mediated endocytosis. Chemoproteomic target deconvolution revealed that reversible modification of lysine residues on the transferrin receptor protein 1 (TFRC) and HLA class I histocompatibility antigen A, B and C (HLA-ABC) enabled efficient uptake and lysosomal targeting through both clathrin-dependent and -independent mechanisms. KB-antibody conjugates (KB-TACs) efficiently degrade the epidermal growth factor receptor (EGFR), vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor 2 (HER2) in cancer cells. Furthermore, we showed KB-TTZ degrades HER2 in vivo in BT-474 tumor xenografts, with a significant reduction in tumor volumes compared to TTZ and vehicle treatments. Altogether, the KB tag represents a versatile, minimal-size chemical unit to functionalize therapeutic antibodies for targeted protein degradation through dual receptor-mediated endocytosis and lysosomal delivery.
Stephan Hacker
Stephan Hacker
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