2 research outputs found
Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3ā3 ProteināProtein Interaction
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 proteināprotein 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 Ī± (ERĪ±) 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
Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3ā3 ProteināProtein Interaction
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 proteināprotein 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 Ī± (ERĪ±) 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