A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
12 Sep 2019
12 Sep 2019
Historique:
received:
08
07
2019
accepted:
16
08
2019
entrez:
19
9
2019
pubmed:
19
9
2019
medline:
19
9
2019
Statut:
epublish
Résumé
The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiological processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences.
Identifiants
pubmed: 31531208
doi: 10.1021/acsmedchemlett.9b00306
pmc: PMC6746191
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1346-1352Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
Références
N Engl J Med. 1999 Apr 8;340(14):1075-9
pubmed: 10194237
Chem Pharm Bull (Tokyo). 1999 Dec;47(12):1778-86
pubmed: 10748721
J Comput Chem. 2004 Oct;25(13):1605-12
pubmed: 15264254
Endocrinology. 2006 Feb;147(2):1044-53
pubmed: 16269450
Pharmacol Rev. 2006 Dec;58(4):760-72
pubmed: 17132853
Bioorg Med Chem Lett. 2007 Jun 15;17(12):3491-6
pubmed: 17490875
Nat Rev Drug Discov. 2007 Oct;6(10):811-20
pubmed: 17906643
Endocrinology. 2009 May;150(5):2368-75
pubmed: 19147676
Nat Neurosci. 2011 Jan;14(1):45-53
pubmed: 21131950
Science. 2012 Mar 23;335(6075):1503-6
pubmed: 22323736
Cell. 2014 Mar 27;157(1):255-66
pubmed: 24679540
J Med Chem. 2014 Jun 26;57(12):5370-80
pubmed: 24801499
Future Med Chem. 2015;7(18):2411-3
pubmed: 26653291
Bioorg Med Chem Lett. 2017 Mar 1;27(5):1193-1198
pubmed: 28169169
J Med Chem. 2017 Jul 13;60(13):5235-5266
pubmed: 28252961
J Med Chem. 2017 Aug 24;60(16):7199-7205
pubmed: 28749691
J Med Chem. 2018 Jun 28;61(12):5442-5447
pubmed: 29901398
Medchemcomm. 2018 Jun 6;9(8):1289-1292
pubmed: 30151082
Sci Rep. 2018 Sep 10;8(1):13554
pubmed: 30202096
J Med Chem. 2019 Feb 28;62(4):2112-2126
pubmed: 30702885
ACS Med Chem Lett. 2019 Jan 04;10(2):203-208
pubmed: 30783504
Methods Mol Biol. 2019;1966:175-192
pubmed: 31041747