PMID- 21381756
OWN - NLM
STAT- MEDLINE
DCOM- 20120312
LR  - 20211020
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Print)
IS  - 1554-8929 (Linking)
VI  - 6
IP  - 6
DP  - 2011 Jun 17
TI  - Identification of a novel non-retinoid pan inverse agonist of the retinoic acid 
      receptors.
PG  - 618-27
LID - 10.1021/cb100396s [doi]
AB  - Retinoids are potent forms of vitamin A and are involved in a broad range of 
      physiological processes and the pharmacological effects of retinoids are 
      primarily mediated by the retinoic acid receptors (RARs) and the retinoid X 
      receptors (RXRs). Several natural and synthetic RAR modulators have proven to be 
      clinically useful for a number of therapeutic indications including cancer, 
      psoriasis, and diabetes. Unfortunately, these agents lead to a number of 
      significant side effects. Most synthetic retinoid ligands are based on the 
      retinoid scaffold and thus have similarities to the natural ligand with all 
      previously disclosed RAR ligands having a carboxylic acid that makes a critical 
      ionic bridge within the ligand binding domain of the receptors. The potential 
      therapeutic value offered from RAR modulation provides the impetus to identify 
      novel ligands based on unique scaffolds that may offer improved toxicity and 
      pharmacokinetic profiles. Here we describe the identification of an atypical RAR 
      inverse agonist that represents the first non-acid, non-retinoid direct modulator 
      of RAR receptor subfamily. SR-0065 functions as a pan-RAR inverse agonist 
      suppressing the basal activity of RARalpha, RARbeta, and RARgamma, as well as inhibiting 
      agonist-induced RAR activity. SR-0065 treatment enhanced receptor interaction 
      with a peptide representative of the corepressor SMRT, and in cells SR-0065 
      enhances recruitment of SMRT to the promoter of the RARgamma dependent gene, Cyp26A1. 
      The acid form of SR-0065, SR-1758, was inactive in all assays. Thus, SR-0065 
      represents a new class of non-acid, non-retinoid RAR modulator that may be used 
      as a point to initiate development of improved RAR-targeted drugs.
FAU - Busby, Scott A
AU  - Busby SA
AD  - Department of Molecular Therapeutics, The Scripps Research Institute, Scripps 
      Florida, Jupiter, FL 33458, United States.
FAU - Kumar, Naresh
AU  - Kumar N
FAU - Kuruvilla, Dana S
AU  - Kuruvilla DS
FAU - Istrate, Monica A
AU  - Istrate MA
FAU - Conkright, Juliana J
AU  - Conkright JJ
FAU - Wang, Yongjun
AU  - Wang Y
FAU - Kamenecka, Theodore M
AU  - Kamenecka TM
FAU - Cameron, Michael D
AU  - Cameron MD
FAU - Roush, William R
AU  - Roush WR
FAU - Burris, Thomas P
AU  - Burris TP
FAU - Griffin, Patrick R
AU  - Griffin PR
LA  - eng
GR  - R01 MH092769/MH/NIMH NIH HHS/United States
GR  - U54 MH084512/MH/NIMH NIH HHS/United States
GR  - GM084041/GM/NIGMS NIH HHS/United States
GR  - DK080201/DK/NIDDK NIH HHS/United States
GR  - R01 GM084041-03/GM/NIGMS NIH HHS/United States
GR  - R01 DK080201/DK/NIDDK NIH HHS/United States
GR  - R01 GM084041/GM/NIGMS NIH HHS/United States
GR  - S10 RR027270/RR/NCRR NIH HHS/United States
GR  - U54 MH074404/MH/NIMH NIH HHS/United States
GR  - U54 MH084512-04/MH/NIMH NIH HHS/United States
GR  - U54MH074404/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110317
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (Dioxanes)
RN  - 0 (Ligands)
RN  - 0 (Quinolones)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (SR-0065)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Dioxanes/chemistry/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Ligands
MH  - Mice
MH  - Molecular Structure
MH  - Quinolones/chemistry/*pharmacology
MH  - Receptors, Retinoic Acid/*agonists
MH  - Retinoid X Receptors/*agonists
MH  - Structure-Activity Relationship
PMC - PMC3117942
MID - NIHMS281424
EDAT- 2011/03/09 06:00
MHDA- 2012/03/13 06:00
PMCR- 2012/06/17
CRDT- 2011/03/09 06:00
PHST- 2011/03/09 06:00 [entrez]
PHST- 2011/03/09 06:00 [pubmed]
PHST- 2012/03/13 06:00 [medline]
PHST- 2012/06/17 00:00 [pmc-release]
AID - 10.1021/cb100396s [doi]
PST - ppublish
SO  - ACS Chem Biol. 2011 Jun 17;6(6):618-27. doi: 10.1021/cb100396s. Epub 2011 Mar 17.