title: Bifunctional ligands allow deliberate extrinsic reprogramming of the glucocorticoid receptor.
abstract: Therapies based on conventional nuclear receptor ligands are extremely powerful, yet their broad and long-term use is often hindered by undesired side effects that are often part of the receptor's biological function. Selective control of nuclear receptors such as the glucocorticoid receptor (GR) using conventional ligands has proven particularly challenging. Because they act solely in an allosteric manner, conventional ligands are constrained to act via cofactors that can intrinsically partner with the receptor. Furthermore, effective means to rationally encode a bias for specific coregulators are generally lacking. Using the (GR) as a framework, we demonstrate here a versatile approach, based on bifunctional ligands, that extends the regulatory repertoire of GR in a deliberate and controlled manner. By linking the macrolide FK506 to a conventional agonist (dexamethasone) or antagonist (RU-486), we demonstrate that it is possible to bridge the intact receptor to either positively or negatively acting coregulatory proteins bearing an FK506 binding protein domain. Using this strategy, we show that extrinsic recruitment of a strong activation function can enhance the efficacy of the full agonist dexamethasone and reverse the antagonist character of RU-486 at an endogenous locus. Notably, the extrinsic recruitment of histone deacetylase-1 reduces the ability of GR to activate transcription from a canonical GR response element while preserving ligand-mediated repression of nuclear factor-κB. By providing novel ways for the receptor to engage specific coregulators, this unique ligand design approach has the potential to yield both novel tools for GR study and more selective therapeutics.
authors.affiliation: Department of Chemistry (J.W.H.,Y.I., J.P.C., A.K.M.), University of Michigan, and Department of Pharmacology (O.C.-R., J.A.I.-L.), University of Michigan Medical School, Ann Arbor, Michigan 48109; and Department of Chemistry and Biochemistry (A.R.V.D.), Fairfield University, Fairfield, Connecticut 06824.
authors.forename: Jonas W
authors.initials: JW
authors.lastname: Højfeldt
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Cruz-Rodríguez
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Van Dyke
authors.forename: James P
authors.initials: JP
authors.lastname: Carolan
authors.forename: Anna K
authors.initials: AK
authors.lastname: Mapp
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Iñiguez-Lluhí
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D002135:Calcium-Binding Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D011965:Receptors, Glucocorticoid; C103003:S100P protein, human; D015735:Mifepristone; D003907:Dexamethasone; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D016559:Tacrolimus