High-Throughput Screening and Proteomic Characterization of Compounds Targeting Myeloid-Derived Suppressor Cells.

Autor:	Krumm J; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany., Petrova E; Global Research & Development, Discovery and Development Technologies, Discovery Pharmacology, Healthcare Business of Merck KGaA, Darmstadt, Germany., Lechner S; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany., Mergner J; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany; Bavarian Center for Biomolecular Mass Spectrometry at Klinikum rechts der Isar (BayBioMS@MRI), Technical University of Munich, Munich, Germany., Boehm HH; Global Research & Development, TIP-Oncology & Immunooncology, Myeloid Cell Research, Healthcare Business of Merck KGaA, Darmstadt, Germany., Prestipino A; Global Research & Development, Discovery and Development Technologies, Discovery Pharmacology, Healthcare Business of Merck KGaA, Darmstadt, Germany., Steinbrunn D; OmicScouts GmbH, Freising, Germany., Deline ML; Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Koetzner L; Global Research & Development, Discovery and Development Technologies, Global Medicinal Chemistry, Healthcare Business of Merck KGaA, Darmstadt, Germany., Schindler C; Global Research & Development, Discovery Technologies, Computational Chemistry & Biologics, Healthcare Business of Merck KGaA, Darmstadt, Germany., Helming L; Global Research & Development, TIP-Oncology & Immunooncology, Myeloid Cell Research, Healthcare Business of Merck KGaA, Darmstadt, Germany., Fromme T; Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany; Else Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany; ZIEL Institute for Food & Health, Technical University of Munich, Freising, Germany., Klingenspor M; Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany; Else Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany; ZIEL Institute for Food & Health, Technical University of Munich, Freising, Germany., Hahne H; OmicScouts GmbH, Freising, Germany., Pieck JC; Global Research & Development, Discovery and Development Technologies, Discovery Pharmacology, Healthcare Business of Merck KGaA, Darmstadt, Germany., Kuster B; Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany; Bavarian Biomolecular Mass Spectrometry Center (BayBioMS), Technical University of Munich, Freising, Germany. Electronic address: kuster@tum.de.
Jazyk:	angličtina
Zdroj:	Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2023 Sep; Vol. 22 (9), pp. 100632. Date of Electronic Publication: 2023 Aug 14.
DOI:	10.1016/j.mcpro.2023.100632
Abstrakt:	Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell population for drug discovery. Here, we characterized the baseline proteomes and phospho-proteomes of mouse MDSC differentiated from a progenitor cell line to a depth of 7000 proteins and phosphorylation sites. We also validated the cellular system for drug discovery by recapitulating and identifying known and novel molecular responses to the well-studied MDSC drugs entinostat and mocetinostat. We established a high-throughput drug screening platform using a MDSC/T cell coculture system and assessed the effects of ∼21,000 small molecule compounds on T cell proliferation and IFN-γ secretion to identify novel MDSC modulator. The most promising candidates were validated in a human MDSC system, and subsequent proteomic experiments showed significant upregulation of several proteins associated with the reduction of reactive oxygen species (ROS). Proteome-wide solvent-induced protein stability assays identified Acyp1 and Cd74 as potential targets, and the ROS-reducing drug phenotype was validated by measuring ROS levels in cells in response to compound, suggesting a potential mode of action. We anticipate that the data and chemical tools developed in this study will be valuable for further research on MDSC and related drug discovery. Competing Interests: Conflict of interest The authors declare the following competing financial interests: B. K. is founder and shareholder of OmicScouts and MSAID. He has no operational role in either company. H. H and D. S are employees of OmicScouts GmbH, Freising, Germany. J. K is currently also an employee of OmicScouts GmbH, Freising, Germany. E. P., H.-H. B, A. P., L. K., C. S., L. H., and J. C. P are employees of Merck KGaA, Darmstadt, Germany. The other authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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