Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD

Jonathan J Sabbagh, Ricardo A Cordova, Dali Zheng, Marangelie Criado-Marrero, Andrea Lemus, Pengfei Li, Jeremy D Baker, Bryce A Nordhues, April L Darling, Carlos Martinez-Licha, Daniel A Rutz, Shreya Patel, etc.

ACS Chem Biol. 2018 Aug 17;13(8):2288-2299.

PMID: 29893552

Abstract:

Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP132172	Benztropine mesylate		132-17-2	Price