Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists

被引:30
作者
Meijer, Femke A. [1 ,2 ]
Doveston, Richard G. [1 ,2 ,3 ,4 ]
de Vries, Rens M. J. M. [1 ,2 ]
Vos, Gael M. [1 ,2 ]
Vos, Alex A. A. [1 ,2 ]
Leysen, Seppe [1 ,2 ]
Scheepstra, Marcel [1 ,2 ]
Ottmann, Christian [1 ,2 ]
Milroy, Lech-Gustav [1 ,2 ]
Brunsveld, Luc [1 ,2 ]
机构
[1] Tech Univ Eindhoven, Lab Chem Biol, Dept Biomed Engn, Dolech 2, NL-5612 AZ Eindhoven, Netherlands
[2] Tech Univ Eindhoven, Inst Complex Mol Syst, Dolech 2, NL-5612 AZ Eindhoven, Netherlands
[3] Univ Leicester, Leicester Inst Struct & Chem Biol, Univ Rd, Leicester LE1 7RH, Leics, England
[4] Univ Leicester, Dept Chem, Univ Rd, Leicester LE1 7RH, Leics, England
关键词
NUCLEAR RECEPTOR; ACCURATE DOCKING; DIFFERENTIATION; MODULATORS; ALPHA; ANTAGONISTS; INTERFACE; DISCOVERY; PROGRAM; PHASE;
D O I
10.1021/acs.jmedchem.9b01372
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of ROR gamma t is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric ROR gamma t inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 (FM26), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EM cells, a marker of ROR gamma t activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the ROR gamma t ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of ROR gamma t.
引用
收藏
页码:241 / 259
页数:19
相关论文
共 52 条
[1]   ChemT, an open-source software for building template-based chemical libraries [J].
Abreu, R. M. V. ;
Froufe, H. J. C. ;
Daniel, P. O. M. ;
Queiroz, M. J. R. P. ;
Ferreira, I. C. F. R. .
SAR AND QSAR IN ENVIRONMENTAL RESEARCH, 2011, 22 (5-6) :603-610
[2]  
[Anonymous], 2000, PYMOL MOL GRAPH SYST
[3]  
Asinex Corp, GOLD PLAT COLL REL 1
[4]   Safety and Efficacy of Brodalumab for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis [J].
Attia, Attia ;
Abushouk, Abdelrahman Ibrahim ;
Ahmed, Hussien ;
Gadelkarim, Mohamed ;
Elgebaly, Ahmed ;
Hassan, Zeinab ;
Abdel-Daim, Mohamed M. ;
Negida, Ahmed .
CLINICAL DRUG INVESTIGATION, 2017, 37 (05) :439-451
[5]   RORγ antagonists and inverse agonists: a patent review [J].
Bronner, Sarah M. ;
Zbieg, Jason R. ;
Crawford, James J. .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2017, 27 (01) :101-112
[6]  
Buckman D. O, 2014, International patent, Patent No. [WO/2014/113485, 113485]
[7]   IL-17 Blockade in Psoriasis [J].
Burkett, Patrick R. ;
Kuchroo, Vijay K. .
CELL, 2016, 167 (07) :1669-1669
[8]   Electron diffraction data processing with DIALS [J].
Clabbers, Max T. B. ;
Gruene, Tim ;
Parkhurst, James M. ;
Abrahams, Jan Pieter ;
Waterman, David G. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2018, 74 :506-518
[9]   PHASE: A novel approach to pharmacophore modeling and 3D database searching [J].
Dixon, Steven L. ;
Smondyrev, Alexander M. ;
Rao, Shashidhar N. .
CHEMICAL BIOLOGY & DRUG DESIGN, 2006, 67 (05) :370-372
[10]   PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results [J].
Dixon, Steven L. ;
Smondyrev, Alexander M. ;
Knoll, Eric H. ;
Rao, Shashidhar N. ;
Shaw, David E. ;
Friesner, Richard A. .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2006, 20 (10-11) :647-671