Development of brain penetrant RXR agonists for neurodegenerative pathologies

• Applicant: Dr. Giuliana Costanzo, Ph.D.
• Subject Area: Pharmacy
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582214514

The nuclear retinoid X receptors regulate gene expression in response to ligands and are considered as promising targets in neurodegenerative diseases such as Alzheimer’s based on results of cellular and preclinical models. However, available RXR ligands comprise an acidic motif and display poor permeation of the blood-brain-barrier (BBB) compromising their suitability for brain-directed effects and further exploration of RXR as target in the CNS. This project aims to develop novel brain-penetrant RXR agonists as chemical tools and leads. The proposed 24-month research plan integrates computer-aided and structure-based design, synthetic chemistry, and pharmacological evaluation to generate non-acidic RXR agonists with improved potency and CNS exposure. Early stages will explore bioisosteric replacement of the acidic residue on two representative RXR agonist scaffolds. Subsequently, the gained knowledge will be transferred to other potent RXR ligand chemotypes to identify optimal leads for systematic optimization towards high potency and brain penetration in the third project phase. In parallel, a non-acidic fragment-like RXR agonist will serve as alternative lead and will be systematically optimized. A co-crystal structure of RXR in complex with this fragment is available to guide analogue design. Optimized brain-penetrant RXR agonist candidates from both approaches will undergo comprehensive in vitro profiling, including broad evaluation of RXR modulation and binding, selectivity, microsomal stability, and BBB permeability. These assays will identify the most promising candidates for evaluation in neuronal models and for in vivo evaluation of brain bioavailability. The expected outcome is a chemically diverse set of potent, selective, and BBB-permeant RXR agonists that will serve as advanced chemical tools to study RXR signaling in the CNS and as starting points for preclinical development of RXR agonists in neurodegenerative pathologies.

• DFG Programme: Position