The nuclear hormone receptor superfamily (NHR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor-related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, metabolism and the immune response. We recently identified the first selective synthetic ligands that target ROR, a critical regulator of the circadian rhythm. Our long-term goal is to develop ligands targeting RORs that can be used to treat diseases associated with dysregulation of the circadian rhythm such as bipolar and sleep disorders as well as schizophrenia. The initial lead compound (T0901317) has less than optimal properties for use as a drug targeting ROR and our preliminary data indicates that we can significantly improve its drug like properties. We hypothesize that optimized ROR ligands, based on the T0901317 chemical scaffold, with improved pharmacodynamic, pharmacokinetic, and receptor selectivity properties will have efficacy in modulation of the circadian rhythm. In order to address this hypothesis we will focus on the following specific aims: 1) Develop and optimize ROR ligands with improved pharmacokinetic and pharmacodynamic properties targeting the central nervous system;2) Characterize the actions of ROR ligands on the circadian rhythm in animals. We predict that this research will provide novel, innovative ligands that modulate ROR1 activity that will have potential utility to treat sleep disorders as well as other disorders associated with dysregulation of the circadian rhythm including biopolar disorder and schizophrenia.

Public Health Relevance

The nuclear hormone receptor superfamily (NHR) has proven to be a rich source of targets for development of drugs that target myriad human diseases and we recently identified the first selective synthetic ligands for the retinoic acid receptor-related orphan receptors (RORs). This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including bipolar and sleep disorders. The goal of this proposal is to develop ROR ligands with optimized pharmacodynamic and pharmacokinetic properties and appropriate receptor selectivity profiles that we will evaluate for their ability to modulate circadian function in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH092769-04
Application #
8586355
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Driscoll, Jamie
Project Start
2010-12-22
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$669,945
Indirect Cost
$331,589
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kojetin, Douglas J; Burris, Thomas P (2014) REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov 13:197-216
Kojetin, Douglas J; Burris, Thomas P (2013) Small molecule modulation of nuclear receptor conformational dynamics: implications for function and drug discovery. Mol Pharmacol 83:1-8
Solt, Laura A; Wang, Yongjun; Banerjee, Subhashis et al. (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485:62-8
Wang, Yongjun; Solt, Laura A; Kojetin, Douglas J et al. (2012) Regulation of p53 stability and apoptosis by a ROR agonist. PLoS One 7:e34921
Kumar, Naresh; Lyda, Brent; Chang, Mi Ra et al. (2012) Identification of SR2211: a potent synthetic ROR?-selective modulator. ACS Chem Biol 7:672-7
Crumbley, Christine; Wang, Yongjun; Banerjee, Subhashis et al. (2012) Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor * (ROR*). PLoS One 7:e33804
Solt, Laura A; Kumar, Naresh; Nuhant, Philippe et al. (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472:491-4
Crumbley, Christine; Burris, Thomas P (2011) Direct regulation of CLOCK expression by REV-ERB. PLoS One 6:e17290
Solt, Laura A; Kojetin, Douglas J; Burris, Thomas P (2011) The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med Chem 3:623-38