7B88

Crystal structure of Retinoic Acid Receptor alpha (RXRA) in complexed with S99 inhibitor

7B88 の概要

• エントリーDOI: 10.2210/pdb7b88/pdb
• 分子名称: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, 3-[5-[3,5-bis(chloranyl)phenyl]-4-phenyl-1,3-oxazol-2-yl]propanoic acid, ... (4 entities in total)
• 機能のキーワード: rxr alpha, rxra, inhibitor, structural genomics, structural genomics consortium, sgc, dna binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27923.23

構造登録者

Chaikuad, A.,Schierle, S.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2020-12-12, 公開日: 2021-01-13, 最終更新日: 2024-01-31)

主引用文献

Schierle, S.,Chaikuad, A.,Lillich, F.F.,Ni, X.,Woltersdorf, S.,Schallmayer, E.,Renelt, B.,Ronchetti, R.,Knapp, S.,Proschak, E.,Merk, D.
Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics.
J.Med.Chem., 64:5123-5136, 2021

PubMed Abstract: 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 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 settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

PubMed: 33793232
DOI: 10.1021/acs.jmedchem.1c00235

実験手法

X-RAY DIFFRACTION (2.38 Å)