PMID- 31531208
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 10
IP  - 9
DP  - 2019 Sep 12
TI  - A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype 
      and Heterodimer Preferences.
PG  - 1346-1352
LID - 10.1021/acsmedchemlett.9b00306 [doi]
AB  - 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.
FAU - Pollinger, Julius
AU  - Pollinger J
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Schierle, Simone
AU  - Schierle S
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Gellrich, Leonie
AU  - Gellrich L
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Ohrndorf, Julia
AU  - Ohrndorf J
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Kaiser, Astrid
AU  - Kaiser A
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Heitel, Pascal
AU  - Heitel P
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Chaikuad, Apirat
AU  - Chaikuad A
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Knapp, Stefan
AU  - Knapp S
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
FAU - Merk, Daniel
AU  - Merk D
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
LA  - eng
PT  - Journal Article
DEP - 20190816
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC6746191
COIS- The authors declare no competing financial interest.
EDAT- 2019/09/19 06:00
MHDA- 2019/09/19 06:01
PMCR- 2020/09/12
CRDT- 2019/09/19 06:00
PHST- 2019/07/08 00:00 [received]
PHST- 2019/08/16 00:00 [accepted]
PHST- 2019/09/19 06:00 [entrez]
PHST- 2019/09/19 06:00 [pubmed]
PHST- 2019/09/19 06:01 [medline]
PHST- 2020/09/12 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.9b00306 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2019 Aug 16;10(9):1346-1352. doi: 
      10.1021/acsmedchemlett.9b00306. eCollection 2019 Sep 12.