Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction.

Autor:	Pallesen JS; Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Munier CC; Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Bosica F; Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Andrei SA; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Edman K; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Gunnarsson A; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., La Sala G; Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Putra OD; Early Product Development and Manufacturing, Pharmaceutical Sciences R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Srdanović S; School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, U.K., Wilson AJ; School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, West Yorkshire LS2 9JT, U.K., Wissler L; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., Ottmann C; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Perry MWD; Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden., O'Mahony G; Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183 Mölndal, Sweden.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Dec 22; Vol. 65 (24), pp. 16818-16828. Date of Electronic Publication: 2022 Dec 09.
DOI:	10.1021/acs.jmedchem.2c01635
Abstrakt:	The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.
Databáze:	MEDLINE
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