BRF110, an Orally Active Nurr1-RXRα-Selective Rexinoid, Enhances BDNF Expression without Elevating Triglycerides
We report the discovery of a Nurr1-RXRα heterodimer-selective rexinoid which emerged from the structural modification of aminopyrimidine XCT0135908. Although XCT0135908 demonstrated high selectivity for the Nurr1-RXRα heterodimer over other RXRα dimerization partners, its poor in vivo stability and limited brain penetration hindered its utility. Structure-activity relationship (SAR) studies alongside bioactivity evaluations of a diverse series of substituted pyrimidines led to BRF110, a brain-penetrant compound retaining the selective activation of the Nurr1-RXRα heterodimer. BRF110, as XCT0135908, protects dopaminergic cells against the Parkinson's disease-related toxin MPP<sup>+</sup> and increases BDNF transcription in mice. Notably, BRF110, in contrast to the market-approved pan-RXR agonist bexarotene, did not elevate triglyceride levels, indicating that enhanced heterodimer selectivity can mitigate off-target in vivo side effects of rexinoids. These findings highlight the potential of heterodimer-selective scaffolds as a strategy for improving the therapeutic profile of rexinoids, addressing significant challenges in the clinical development of RXR-targeting molecules.
Authors
- Xenophon Asvos
- Athanasios Papakyriakou (ORCID: https://orcid.org/0000-0003-3931-6232)
- Mohamed A. El Mubarak (ORCID: https://orcid.org/0000-0002-2575-3565)
- Gregory Sivolapenko (ORCID: https://orcid.org/0000-0003-2388-362X)
- Stavros Topouzis (ORCID: https://orcid.org/0000-0001-5443-5016)
- Demosthenes Fokas (ORCID: https://orcid.org/0009-0004-6039-5048)
- Constantin Tamvakopoulos (ORCID: https://orcid.org/0000-0001-9627-4812)
- Theodoros Karampelas (ORCID: https://orcid.org/0000-0002-2825-7188)
- Demetrios K. Vassilatis (ORCID: https://orcid.org/0000-0003-1147-321X)
- Θεόδωρος Ράμπιας (ORCID: https://orcid.org/0000-0002-5460-5334)
Institutions
- University of Patras (GR)
- University of Ioannina (GR)
- National Centre of Scientific Research "Demokritos" (GR)
- Academy of Athens (GR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Center for Clinical Research (United States) (US)
- Institute of Biosciences & Applications
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03046
- Citations
- 8
- Primary Topic
- Nuclear Receptors and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 7.27
Funders
- Michael J. Fox Foundation for Parkinson's Research
- University of Patras
- Hellenic Academic Libraries Link
- General Secretariat for Research and Technology
- Centre National de la Recherche Scientifique
- University of Ioannina
- Seventh Framework Programme