8PP0

Crystal structure of Retinoic Acid Receptor alpha (RXRA) in complexed with JP147

Summary for 8PP0

• Entry DOI: 10.2210/pdb8pp0/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, 3-[4-[2,3-dihydro-1H-inden-4-yl(methyl)amino]-6-(trifluoromethyl)pyrimidin-2-yl]oxypropanoic acid, ... (4 entities in total)
• Functional Keywords: rxr alpha, inhibitor, structural genomics, structural genomics consortium, sgc, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 29198.70

Authors

Chaikuad, A.,Pollinger, J.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-07-05, release date: 2024-02-07, Last modification date: 2024-02-21)

Primary citation

Lewandowski, M.,Carmina, M.,Knumann, L.,Sai, M.,Willems, S.,Kasch, T.,Pollinger, J.,Knapp, S.,Marschner, J.A.,Chaikuad, A.,Merk, D.
Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties.
J.Med.Chem., 67:2152-2164, 2024

PubMed Abstract: Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9- 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.

PubMed: 38237049
DOI: 10.1021/acs.jmedchem.3c02095

Experimental method

X-RAY DIFFRACTION (1.9 Å)