Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists
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...
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| Vydané v: | Journal of medicinal chemistry Ročník 63; číslo 1; s. 241 - 259 |
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| Hlavní autori: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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Amer Chemical Soc
09.01.2020
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| ISSN: | 0022-2623, 1520-4804, 1520-4804 |
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| Abstract | 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. |
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| AbstractList | Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt 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 RORγt 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 EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt 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 RORγt.Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt 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 RORγt 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 EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt 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 RORγt. 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. Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt 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 RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, ( ), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of was confirmed by biochemical experiments and cocrystallization with the RORγt 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 RORγt. |
| Author | Meijer, Femke A. Leysen, Seppe Scheepstra, Marcel Milroy, Lech-Gustav Brunsveld, Luc Doveston, Richard G. Ottmann, Christian Vos, Alex A. A. de Vries, Rens M. J. M. Vos, Gael M. |
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| Cites_doi | 10.1016/j.jdermsci.2019.03.002 10.1021/jm030644s 10.1038/nrd3794 10.1021/jm0306430 10.1021/acs.jmedchem.8b01567 10.1016/j.cell.2016.11.044 10.1007/s10822-006-9087-6 10.1080/13543776.2017.1236918 10.1038/ncomms9833 10.1016/j.immuni.2007.11.016 10.1107/S2059798318007726 10.1210/me.2009-0362 10.1016/j.bmcl.2016.10.023 10.1517/13543776.2015.1065816 10.1021/jm401901d 10.1107/S0907444910007493 10.1124/mol.109.060905 10.1016/j.it.2017.02.006 10.1016/j.bmcl.2019.04.021 10.1016/j.mce.2019.01.022 10.1016/j.cell.2006.07.035 10.1038/nm0502-500 10.1038/nature09978 10.1126/science.1135245 10.1107/S0907444911001314 10.1111/j.1747-0285.2006.00384.x 10.1136/annrheumdis-2016-209709 10.1038/nrd2199 10.1126/scitranslmed.3001107 10.1038/nm.4070 10.1016/j.celrep.2016.11.073 10.1038/NCHEMBIO.1714 10.1038/nrd1551 10.1107/S2059798317016035 10.1002/chem.201402559 10.1080/1062936X.2011.604097 10.1021/acs.jmedchem.8b00588 10.1038/ni.1610 10.1074/jbc.M117.789024 10.1002/cmdc.201100522 10.1021/acs.jmedchem.9b00327 10.1107/S2059798317000067 10.1107/S0907444906045975 10.1016/j.ejmech.2019.01.082 10.1021/acsmedchemlett.9b00010 10.1007/s40261-017-0500-9 10.1016/j.bmcl.2016.07.067 |
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| References | Burkett, PR (WOS:000393114700003) 2016; 167 Hu, X (WOS:000348358800012) 2015; 11 Hueber, W (WOS:000288438800003) 2010; 2 LEROY J (WOS:000507150400016.29) 1997; 74 Tanis, VM (WOS:000466365200007) 2019; 29 Dixon, SL (WOS:000239311000008) 2006; 67 McCoy, AJ (WOS:000242796000005) 2007; 63 Yang, XXO (WOS:000252627300008) 2008; 28 Pandya, VB (WOS:000454751100003) 2018; 61 Kalin, JH (WOS:000300942300011) 2012; 7 Huh, JR (WOS:000289949600037) 2011; 472 Moore, TW (WOS:000276051300001) 2010; 24 (000507150400016.1) 2014 Zhang, Y (WOS:000467781700029) 2019; 62 Tian, JL (WOS:000461728400003) 2019; 167 Oakdale, JS (WOS:000340902800030) 2014; 20 Lock, C (WOS:000175336800036) 2002; 8 Scheepstra, M (WOS:000367585400001) 2015; 6 Li, X (WOS:000405485600003) 2017; 292 Duan, JJW (WOS:000461537500025) 2019; 10 Ouvry, G (WOS:000389519100036) 2016; 26 Asinex Corp. (000507150400016.2) 1000 Attia, A (WOS:000399679600003) 2017; 37 Miossec, P (WOS:000309515900020) 2012; 11 Friesner, RA (WOS:000220317600019) 2004; 47 Mease, PJ (WOS:000392425200012) 2017; 76 Bronner, SM (WOS:000391474700009) 2017; 27 Gronemeyer, H (WOS:000224833100019) 2004; 3 Meijer, FA (WOS:000459926500003) 2019; 485 Fauber, BP (WOS:000339540800004) 2014; 57 Wang, JJ (WOS:000375514000011) 2016; 22 Abreu, RMV (WOS:000299560600010) 2011; 22 Overington, JP (WOS:000242478300012) 2006; 5 Zhong, C (WOS:000398184700001) 2017; 38 Long, F (WOS:000396209000004) 2017; 73 Guo, YX (WOS:000390895600012) 2016; 17 Clabbers, MTB (WOS:000434348800003) 2018; 74 Duerr, RH (WOS:000242406100044) 2006; 314 Halgren, TA (WOS:000220317600020) 2004; 47 Harris, JM (WOS:000175293500009) 2002; 16 Ivanov, II (WOS:000240897600018) 2006; 126 Dixon, SL (WOS:000243047000004) 2006; 20 Imura, C (WOS:000469408300005) 2019; 93 (000507150400016.3) 2000 Tice, CM (WOS:000381959900001) 2016; 26 Kumar, N (WOS:000273725600013) 2010; 77 Murshudov, GN (WOS:000288532800015) 2011; 67 Manel, N (WOS:000256067900014) 2008; 9 Emsley, P (WOS:000275941300018) 2010; 66 Potterton, L (WOS:000426842000002) 2018; 74 Kotoku, M (WOS:000461537000040) 2019; 62 Gege, C (WOS:000369387300004) 2015; 25 |
| References_xml | – volume: 93 start-page: 176 year: 2019 ident: WOS:000469408300005 article-title: A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations publication-title: JOURNAL OF DERMATOLOGICAL SCIENCE doi: 10.1016/j.jdermsci.2019.03.002 – volume: 47 start-page: 1750 year: 2004 ident: WOS:000220317600020 article-title: Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm030644s – volume: 11 start-page: 763 year: 2012 ident: WOS:000309515900020 article-title: Targeting IL-17and TH17 cells in chronic inflammation publication-title: NATURE REVIEWS DRUG DISCOVERY doi: 10.1038/nrd3794 – volume: 47 start-page: 1739 year: 2004 ident: WOS:000220317600019 article-title: Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm0306430 – volume: 62 start-page: 2837 year: 2019 ident: WOS:000461537000040 article-title: Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.8b01567 – volume: 167 start-page: 1669 year: 2016 ident: WOS:000393114700003 article-title: IL-17 Blockade in Psoriasis publication-title: CELL doi: 10.1016/j.cell.2016.11.044 – volume: 74 start-page: 212 year: 1997 ident: WOS:000507150400016.29 publication-title: ORG SYNTH – volume: 20 start-page: 647 year: 2006 ident: WOS:000243047000004 article-title: PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results publication-title: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN doi: 10.1007/s10822-006-9087-6 – volume: 27 start-page: 101 year: 2017 ident: WOS:000391474700009 article-title: RORγ antagonists and inverse agonists: a patent review publication-title: EXPERT OPINION ON THERAPEUTIC PATENTS doi: 10.1080/13543776.2017.1236918 – volume: 6 start-page: ARTN 8833 year: 2015 ident: WOS:000367585400001 article-title: Identification of an allosteric binding site for RORγt inhibition publication-title: NATURE COMMUNICATIONS doi: 10.1038/ncomms9833 – volume: 28 start-page: 29 year: 2008 ident: WOS:000252627300008 article-title: T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ publication-title: IMMUNITY doi: 10.1016/j.immuni.2007.11.016 – volume: 74 start-page: 506 year: 2018 ident: WOS:000434348800003 article-title: Electron diffraction data processing with DIALS publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY doi: 10.1107/S2059798318007726 – volume: 24 start-page: 683 year: 2010 ident: WOS:000276051300001 article-title: Minireview: Not Picking Pockets: Nuclear Receptor Alternate-Site Modulators (NRAMs) publication-title: MOLECULAR ENDOCRINOLOGY doi: 10.1210/me.2009-0362 – volume: 16 start-page: 998 year: 2002 ident: WOS:000175293500009 article-title: Characterization of the retinoid orphan-related receptor-α coactivator binding interface: A structural basis for ligand-independent transcription publication-title: MOLECULAR ENDOCRINOLOGY – volume: 26 start-page: 5802 year: 2016 ident: WOS:000389519100036 article-title: Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2016.10.023 – volume: 25 start-page: 1215 year: 2015 ident: WOS:000369387300004 article-title: Retinoid-related orphan receptor γ t modulators: comparison of Glenmark's me-too patent application (WO2015008234) with the originator application from Merck Sharp and Dohme (WO2012106995) publication-title: EXPERT OPINION ON THERAPEUTIC PATENTS doi: 10.1517/13543776.2015.1065816 – volume: 57 start-page: 5871 year: 2014 ident: WOS:000339540800004 article-title: Modulators of the Nuclear Receptor Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/jm401901d – volume: 66 start-page: 486 year: 2010 ident: WOS:000275941300018 article-title: Features and development of Coot publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY doi: 10.1107/S0907444910007493 – volume: 77 start-page: 228 year: 2010 ident: WOS:000273725600013 article-title: The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist publication-title: MOLECULAR PHARMACOLOGY doi: 10.1124/mol.109.060905 – volume: 38 start-page: 229 year: 2017 ident: WOS:000398184700001 article-title: Small-Molecule RORγt Antagonists: One Stone Kills Two Birds publication-title: TRENDS IN IMMUNOLOGY doi: 10.1016/j.it.2017.02.006 – volume: 29 start-page: 1463 year: 2019 ident: WOS:000466365200007 article-title: 3-Substituted Quinolines as RORγt Inverse Agonists publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2019.04.021 – year: 1000 ident: 000507150400016.2 article-title: Gold and platinum collections, release: 1994-2004 publication-title: GOLD PLAT COLL REL 1 – volume: 485 start-page: 20 year: 2019 ident: WOS:000459926500003 article-title: Allosteric small molecule modulators of nuclear receptors publication-title: MOLECULAR AND CELLULAR ENDOCRINOLOGY doi: 10.1016/j.mce.2019.01.022 – volume: 126 start-page: 1121 year: 2006 ident: WOS:000240897600018 article-title: The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells publication-title: CELL doi: 10.1016/j.cell.2006.07.035 – volume: 8 start-page: 500 year: 2002 ident: WOS:000175336800036 article-title: Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis publication-title: NATURE MEDICINE doi: 10.1038/nm0502-500 – volume: 472 start-page: 486 year: 2011 ident: WOS:000289949600037 article-title: Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity publication-title: NATURE doi: 10.1038/nature09978 – volume: 314 start-page: 1461 year: 2006 ident: WOS:000242406100044 article-title: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene publication-title: SCIENCE doi: 10.1126/science.1135245 – year: 2000 ident: 000507150400016.3 article-title: The PyMOL Molecular Graphics System publication-title: PYMOL MOL GRAPH SYST – volume: 67 start-page: 355 year: 2011 ident: WOS:000288532800015 article-title: REFMAC5 for the refinement of macromolecular crystal structures publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY doi: 10.1107/S0907444911001314 – volume: 67 start-page: 370 year: 2006 ident: WOS:000239311000008 article-title: PHASE: A novel approach to pharmacophore modeling and 3D database searching publication-title: CHEMICAL BIOLOGY & DRUG DESIGN doi: 10.1111/j.1747-0285.2006.00384.x – volume: 76 start-page: 79 year: 2017 ident: WOS:000392425200012 article-title: Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1 publication-title: ANNALS OF THE RHEUMATIC DISEASES doi: 10.1136/annrheumdis-2016-209709 – volume: 5 start-page: 993 year: 2006 ident: WOS:000242478300012 article-title: Opinion - How many drug targets are there? publication-title: NATURE REVIEWS DRUG DISCOVERY doi: 10.1038/nrd2199 – volume: 2 start-page: ARTN 52ra72 year: 2010 ident: WOS:000288438800003 article-title: Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis publication-title: SCIENCE TRANSLATIONAL MEDICINE doi: 10.1126/scitranslmed.3001107 – volume: 22 start-page: 488 year: 2016 ident: WOS:000375514000011 article-title: ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer publication-title: NATURE MEDICINE doi: 10.1038/nm.4070 – volume: 17 start-page: 3206 year: 2016 ident: WOS:000390895600012 article-title: Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity publication-title: CELL REPORTS doi: 10.1016/j.celrep.2016.11.073 – volume: 11 start-page: 141 year: 2015 ident: WOS:000348358800012 article-title: Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists publication-title: NATURE CHEMICAL BIOLOGY doi: 10.1038/NCHEMBIO.1714 – volume: 3 start-page: 950 year: 2004 ident: WOS:000224833100019 article-title: Principles for modulation of the nuclear receptor superfamily publication-title: NATURE REVIEWS DRUG DISCOVERY doi: 10.1038/nrd1551 – volume: 74 start-page: 68 year: 2018 ident: WOS:000426842000002 article-title: CCP4i2: the new graphical user interface to the CCP4 program suite publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY doi: 10.1107/S2059798317016035 – volume: 20 start-page: 11101 year: 2014 ident: WOS:000340902800030 article-title: Ruthenium-Catalyzed Cycloadditions of 1-Haloalkynes with Nitrile Oxides and Organic Azides: Synthesis of 4-Haloisoxazoles and 5-Halotriazoles publication-title: CHEMISTRY-A EUROPEAN JOURNAL doi: 10.1002/chem.201402559 – volume: 22 start-page: 603 year: 2011 ident: WOS:000299560600010 article-title: ChemT, an open-source software for building template-based chemical libraries publication-title: SAR AND QSAR IN ENVIRONMENTAL RESEARCH doi: 10.1080/1062936X.2011.604097 – year: 2014 ident: 000507150400016.1 article-title: Lysophosphatidic acid receptor antagonists publication-title: International patent – volume: 61 start-page: 10976 year: 2018 ident: WOS:000454751100003 article-title: Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.8b00588 – volume: 9 start-page: 641 year: 2008 ident: WOS:000256067900014 article-title: The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt publication-title: NATURE IMMUNOLOGY doi: 10.1038/ni.1610 – volume: 292 start-page: 11618 year: 2017 ident: WOS:000405485600003 article-title: Structural studies unravel the active conformation of apo RORγt nuclear receptor and a common inverse agonism of two diverse classes of RORγt inhibitors publication-title: JOURNAL OF BIOLOGICAL CHEMISTRY doi: 10.1074/jbc.M117.789024 – volume: 7 start-page: 425 year: 2012 ident: WOS:000300942300011 article-title: Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress publication-title: CHEMMEDCHEM doi: 10.1002/cmdc.201100522 – volume: 62 start-page: 4716 year: 2019 ident: WOS:000467781700029 article-title: Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer publication-title: JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1021/acs.jmedchem.9b00327 – volume: 73 start-page: 112 year: 2017 ident: WOS:000396209000004 article-title: AceDRG: a stereochemical description generator for ligands publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY doi: 10.1107/S2059798317000067 – volume: 63 start-page: 32 year: 2007 ident: WOS:000242796000005 article-title: Solving structures of protein complexes by molecular replacement with Phaser publication-title: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY doi: 10.1107/S0907444906045975 – volume: 167 start-page: 37 year: 2019 ident: WOS:000461728400003 article-title: Discovery of N-indanyl benzamides as potent RORγt inverse agonists publication-title: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY doi: 10.1016/j.ejmech.2019.01.082 – volume: 10 start-page: 367 year: 2019 ident: WOS:000461537500025 article-title: Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yI)sulfones as Selective, Orally Active RORγt Inverse Agonists publication-title: ACS MEDICINAL CHEMISTRY LETTERS doi: 10.1021/acsmedchemlett.9b00010 – volume: 37 start-page: 439 year: 2017 ident: WOS:000399679600003 article-title: Safety and Efficacy of Brodalumab for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis publication-title: CLINICAL DRUG INVESTIGATION doi: 10.1007/s40261-017-0500-9 – volume: 26 start-page: 4157 year: 2016 ident: WOS:000381959900001 article-title: Non-canonical modulators of nuclear receptors publication-title: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS doi: 10.1016/j.bmcl.2016.07.067 |
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| Title | Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists |
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