Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.

The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.

Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism.

Nuclear receptor related 1 (Nurr1, NR4A2) is a ligand-sensing transcription factor with neuroprotective and anti-inflammatory roles widely distributed in the CNS. Pharmacological Nurr1 modulation is considered a promising experimental strategy in Parkinson's and Alzheimer's disease but target validation is incomplete. While significant progress has been made in Nurr1 agonist development, inverse agonists blocking the receptor's constitutive activity are lacking. Here we report comprehensive structure-activity relationship elucidation of oxaprozin which acts as moderately potent and nonselective inverse Nurr1 agonist and RXR agonist. We identified structural determinants selectively driving RXR agonism or inverse Nurr1 agonism of the scaffold enabling the development of selective inverse Nurr1 agonists with enhanced potency and strong efficacy.

Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.

Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics, and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here, we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists. Focused structure-activity relationship elucidation and rigidization resulted in a substantially optimized partial RXR agonist with low nanomolar potency, no cytotoxic activity, and very favorable physicochemical properties highlighting this promising scaffold for the development of next-generation RXR targeting drugs.

Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency.

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.