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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics.
Cell Rep
June 2024
Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Bavaria, Germany; German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany. Electronic address:
Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus.
View Article and Find Full Text PDFDecrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics.
Nat Biotechnol
May 2024
Chair of Proteomics and Bioanalytics, School of Life Sciences, Technical University of Munich, Freising, Germany.
Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App.
View Article and Find Full Text PDFGlycolytic reprogramming fuels myeloid cell-driven hypercoagulability.
J Thromb Haemost
February 2024
Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland Crumlin, Dublin, Ireland. Electronic address:
Background: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood.
Objectives: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation.
Methods: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease.
CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer.
Mol Cancer Res
November 2023
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina.
Unlabelled: PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects.
View Article and Find Full Text PDFDecrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations.
J Chem Inf Model
June 2023
AlloCyte Pharmaceuticals AG, Hochbergerstrasse 60C, CH-4057 Basel, Switzerland.
Integrins are a family of α/β heterodimeric cell surface adhesion receptors which are capable of transmitting signals bidirectionally across membranes. They are known for their therapeutic potential in a wide range of diseases. However, the development of integrin-targeting medications has been impacted by unexpected downstream effects including unwanted agonist-like effects.
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