PMID- 38064686
OWN - NLM
STAT- MEDLINE
DCOM- 20231229
LR  - 20240301
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 66
IP  - 24
DP  - 2023 Dec 28
TI  - Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist 
      Potency.
PG  - 16762-16771
LID - 10.1021/acs.jmedchem.3c01435 [doi]
AB  - The retinoid X receptors (RXRs) are ligand-activated transcription factors 
      involved in, for example, differentiation and apoptosis regulation. Currently 
      used reference RXR agonists suffer from insufficient specificity and poor 
      physicochemical properties, and improved tools are needed to capture the 
      unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands 
      and the natural product RXR agonist valerenic acid comprise acrylic acid residues 
      with varying substitution patterns to engage the critical ionic contact with the 
      binding site arginine. To mimic and exploit this natural ligand motif, we probed 
      its structural fusion with synthetic RXR modulator scaffolds, which had profound 
      effects on agonist activity and remarkably boosted potency of an 
      oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic 
      acid to overcome its pan-assay interference compounds (PAINS) character enabled 
      the development of a highly optimized RXR agonist chemical probe.
FAU - Adouvi, Gustave
AU  - Adouvi G
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 
      Frankfurt, Germany.
FAU - Nawa, Felix
AU  - Nawa F
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Ballarotto, Marco
AU  - Ballarotto M
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Ruger, Lorena Andrea
AU  - Ruger LA
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 
      Frankfurt, Germany.
FAU - Knumann, Loris
AU  - Knumann L
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Kasch, Till
AU  - Kasch T
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Arifi, Silvia
AU  - Arifi S
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 
      Frankfurt, Germany.
FAU - Schubert-Zsilavecz, Manfred
AU  - Schubert-Zsilavecz M
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 
      Frankfurt, Germany.
FAU - Willems, Sabine
AU  - Willems S
AUID- ORCID: 0000-0002-9755-3394
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Marschner, Julian A
AU  - Marschner JA
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Pabel, Jorg
AU  - Pabel J
AUID- ORCID: 0000-0002-0174-9772
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
FAU - Merk, Daniel
AU  - Merk D
AUID- ORCID: 0000-0002-5359-8128
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 
      Frankfurt, Germany.
AD  - Department of Pharmacy, Ludwig-Maximilians-Universitat Munchen, 81377 Munich, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231208
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Receptors, Retinoic Acid)
RN  - J94PBK7X8S (acrylic acid)
RN  - 0 (Ligands)
RN  - 0 (Acrylates)
RN  - 0 (Retinoid X Receptors)
SB  - IM
MH  - *Receptors, Retinoic Acid/agonists
MH  - Ligands
MH  - *Acrylates
MH  - Retinoid X Receptors/metabolism
EDAT- 2023/12/08 18:42
MHDA- 2023/12/29 06:43
CRDT- 2023/12/08 16:43
PHST- 2023/12/29 06:43 [medline]
PHST- 2023/12/08 18:42 [pubmed]
PHST- 2023/12/08 16:43 [entrez]
AID - 10.1021/acs.jmedchem.3c01435 [doi]
PST - ppublish
SO  - J Med Chem. 2023 Dec 28;66(24):16762-16771. doi: 10.1021/acs.jmedchem.3c01435. 
      Epub 2023 Dec 8.