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Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

René O, Fauber BP, Boenig Gde L, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Kiefer JR, Liimatta M, Lockey P, Norman M, Ouyang W, Wallweber HA, Wong H
ACS Med Chem Lett 6 276-81 (2015)
Cited: 38 times
EuropePMC logo PMID: 25815138

Abstract

A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

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Reviews citing this publication (3)

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  3. (Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease. Jetten AM, Cook DN. Annu Rev Pharmacol Toxicol 60 371-390 (2020)

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  3. Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors. Baviskar AT, Amrutkar SM, Trivedi N, Chaudhary V, Nayak A, Guchhait SK, Banerjee UC, Bharatam PV, Kundu CN. ACS Med Chem Lett 6 481-485 (2015)
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  6. Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORγ. Olsson RI, Xue Y, von Berg S, Aagaard A, McPheat J, Hansson EL, Bernström J, Hansson P, Jirholt J, Grindebacke H, Leffler A, Chen R, Xiong Y, Ge H, Hansson TG, Narjes F. ChemMedChem 11 207-216 (2016)
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  12. Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand. Marcotte DJ, Liu Y, Little K, Jones JH, Powell NA, Wildes CP, Silvian LF, Chodaparambil JV. BMC Struct Biol 16 7 (2016)
  13. Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening. Rauhamäki S, Postila PA, Lätti S, Niinivehmas S, Multamäki E, Liedl KR, Pentikäinen OT. ACS Omega 3 6259-6266 (2018)
  14. From RORγt Agonist to Two Types of RORγt Inverse Agonists. Wang Y, Cai W, Tang T, Liu Q, Yang T, Yang L, Ma Y, Zhang G, Huang Y, Song X, Orband-Miller LA, Wu Q, Zhou L, Xiang Z, Xiang JN, Leung S, Shao L, Lin X, Lobera M, Ren F. ACS Med Chem Lett 9 120-124 (2018)
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  16. Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation. Sun N, Yuan C, Ma X, Wang Y, Gu X, Fu W. Molecules 23 E3181 (2018)
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  18. Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt. Kummer DA, Cummings MD, Abad M, Barbay J, Castro G, Wolin R, Kreutter KD, Maharoof U, Milligan C, Nishimura R, Pierce J, Schalk-Hihi C, Spurlino J, Urbanski M, Venkatesan H, Wang A, Woods C, Xue X, Edwards JP, Fourie AM, Leonard K. Bioorg Med Chem Lett 27 2047-2057 (2017)
  19. GPCR_LigandClassify.py; a rigorous machine learning classifier for GPCR targeting compounds. Ahmed M, Hasani HJ, Kalyaanamoorthy S, Barakat K. Sci Rep 11 9510 (2021)
  20. Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists. Fauber BP, Gobbi A, Savy P, Burton B, Deng Y, Everett C, La H, Johnson AR, Lockey P, Norman M, Wong H. Bioorg Med Chem Lett 25 4109-4113 (2015)
  21. Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats. van Tok MN, Mandour M, Wahle J, Labadia ME, van de Sande MGH, Nabozny G, Baeten DL, van Duivenvoorde LM. Front Immunol 12 699987 (2021)
  22. Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties. René O, Fauber BP, Barnard A, Chapman K, Deng Y, Eidenschenk C, Everett C, Gobbi A, Johnson AR, La H, Norman M, Salmon G, Summerhill S, Wong H. Bioorg Med Chem Lett 26 4455-4461 (2016)
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  24. Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with "short" and "long" inverse agonists. Yu MC, Yang F, Ding XY, Sun NN, Jiang ZY, Huang YF, Yan YR, Zhu C, Xie Q, Chen ZF, Guo SQ, Jiang HL, Chen KX, Luo C, Luo XM, Chen SJ, Wang YH. Acta Pharmacol Sin 42 1524-1534 (2021)
  25. Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting RORγ/IL-17A axis. Tian SY, Chen SM, Feng YY, He JL, Li Y. Acta Pharmacol Sin 44 1217-1226 (2023)
  26. Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc. Wang YN, Ruan DY, Wang ZX, Yu K, Rong DL, Liu ZX, Wang F, Hu JJ, Jin Y, Wu QN, Pu HY, Wang M, Xu RH, Zeng ZL. Oncogene 41 5266-5278 (2022)


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