Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 8, Pages 5123-5136Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00235
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Funding
- German Research Foundation (DFG) [ME5481/1-1, PR1405/7-1]
- Aventis Foundation
- AbbVie
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN] [875510]
- Janssen
- Merck KGaA (aka EMD in Canada)
- Merck & Co (aka MSD outside Canada)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- German translational cancer network DKTK
- Frankfurt Cancer Institute (FCI)
- SGC [1097737]
- Merck KGaA (aka EMD in US)
- Merck & Co (aka MSD outside US)
- University of Perugia
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RXR serves as universal heterodimer partners for nuclear receptors, showing high therapeutic potential but limited by current agonists. Development of new RXR ligands based on oxaprozin led to optimized compounds with improved in vivo properties and high selectivity for RXR activation.
The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.
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