期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 24, 页码 16818-16828出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01635
关键词
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资金
- Initial Training Network TASPPI - H2020 Marie Curie Actions of the European Commission [675179]
- AstraZeneca
The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids. GR is also regulated through protein-protein interactions (PPIs) with adapter proteins 14-3-3 outside the steroid-binding site, providing insights into noncanonical GR signaling and enabling the development of novel GR modulators.
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 alpha (ER alpha) 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.
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