5JY3

CRYSTAL STRUCTURE OF LXRbeta (NUCLEAR RECEPTOR SUBFAMILY 1, GROUP H, MEMBER 2) COMPLEXED WITH BMS-852927

Summary for 5JY3

• Entry DOI: 10.2210/pdb5jy3/pdb
• Descriptor: Oxysterols receptor LXR-beta, 2-[2-[2-[2,6-bis(chloranyl)phenyl]propan-2-yl]-1-[2-fluoranyl-4-[3-fluoranyl-4-(hydroxymethyl)-5-methylsulfonyl-phenyl] phenyl]imidazol-4-yl]propan-2-ol, 1,4-BUTANEDIOL, ... (4 entities in total)
• Functional Keywords: nhr, nr1h2, lxr-b, lxrb, unr, ner-i, rip15, ner, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P55055
• Total number of polymer chains: 4
• Total formula weight: 124789.70

Authors

Muckelbauer, J.K. (deposition date: 2016-05-13, release date: 2016-11-02, Last modification date: 2024-03-06)

Primary citation

Kick, E.K.,Busch, B.B.,Martin, R.,Stevens, W.C.,Bollu, V.,Xie, Y.,Boren, B.C.,Nyman, M.C.,Nanao, M.H.,Nguyen, L.,Plonowski, A.,Schulman, I.G.,Yan, G.,Zhang, H.,Hou, X.,Valente, M.N.,Narayanan, R.,Behnia, K.,Rodrigues, A.D.,Brock, B.,Smalley, J.,Cantor, G.H.,Lupisella, J.,Sleph, P.,Grimm, D.,Ostrowski, J.,Wexler, R.R.,Kirchgessner, T.,Mohan, R.
Discovery of Highly Potent Liver X Receptor beta Agonists.
ACS Med Chem Lett, 7:1207-1212, 2016

PubMed Abstract: Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist . The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist was selected for clinical development based on the favorable combination of properties, excellent pharmacokinetic parameters, and a favorable lipid profile.

PubMed: 27994765
DOI: 10.1021/acsmedchemlett.6b00234

Experimental method

X-RAY DIFFRACTION (2.4 Å)