Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc

Fauber, Benjamin P.; Boenig, Gladys de Leon; Burton, Brenda; Eidenschenk, Céline; Everett, Christine; Gobbi, A.; Hymowitz, S.G.; Johnson, Adam R.; Liimatta, Marya; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; René, Olivier; Wong, Harvey

doi:10.1016/j.bmcl.2013.10.054

Cited by 60 publications

(52 citation statements)

References 37 publications

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“…14 Digoxin, 15 SR1001 16 and Ursolic acid 17 were firstly reported to inhibit RORt and ameliorate EAE in mice via intraperitoneal administration. Afterwards, more small molecular RORt inhibitors [18][19][20][21][22][23][24][25][26] were disclosed and some of them were shown to suppress Th17 cell differentiation in vitro. Recently, we reported the identification of a novel RORt inverse agonist hit (1) through high throughput screening (HTS) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

Wang

Yang

Liu

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

Wang

Yang

Liu

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Crystal structure of the LBD of RORg with TO901317 showed that binding site of this compound is same as cholesterol binding site. 26 To corroborate this structural information, ligand competitive assay for TO901317 was conducted in TopFluor cholesterol binding assay. As expected, the IC 50 value of TO901317 was right-ward shifted depending on increasing TopFluor cholesterol concentration (Fig.…”

Section: Selection Of the Human Rorgt Protein For Htsmentioning

confidence: 98%

Cholesterol Unbound RORγt Protein Enables a Sensitive Inverse Agonist Screening

Koyama

Fukuda

Kamada

et al. 2018

ASSAY and Drug Development Technologies

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The retinoic acid-related orphan receptor gamma T (RORγt) plays an important role in Th17 cell proliferation and functionality. Thus, RORγt inverse agonists are thought to be potent therapeutic agents for Th17-mediated autoimmune diseases, such as rheumatoid arthritis, asthma, inflammatory bowel disease, and psoriasis. Although RORγt has constitutive activity, it is recognized that the receptor is physiologically regulated by various cholesterol derivatives. In this study, we sought to identify RORγt inverse agonists through a high-throughput screening campaign. To this end, we compared an apo-RORγt protein from Escherichia coli and a cholesterol-bound RORγt protein from insect cells. The IC of the known RORγt inverse agonist TO901317 was significantly lower for the apoprotein than for the cholesterol-bound RORγt. Through high-throughput screening using a fluorescence-based cholesterol binding assay with the apoprotein, we identified compound 1 as a novel cholesterol-competitive RORγt inverse agonist. Compound 1 inhibited the RORγt-TopFluor cholesterol interaction, coactivator recruitment, and transcriptional activity of RORγt. Cell-based reporter gene assay demonstrated that compound 1 showed higher potency by lipid depletion treatment. Collectively, our findings indicate that eliminating cholesterol from the RORγt protein is suitable for sensitive high-throughput screening to identify RORγt inverse agonists.

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“…A team from Genentech identified N-isobutyl-N-((5-(4-(methylsulfonyl)phenyl)thiophen-2-yl)methyl)-1-phenylmethanesulfonamide as RORc inverse agonist (7, Figure 1) via a biochemical screening campaign [20] . Although the development of RORc inverse agonists has shown significant promise [21,22] , the development of new RORc selective modulators with therapeutic potential still remains an urgent need.…”

Section: Original Articlementioning

confidence: 99%

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists

Wang

Xing

et al. 2016

Acta Pharmacol Sin

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Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc

Cited by 60 publications

References 37 publications

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

Cholesterol Unbound RORγt Protein Enables a Sensitive Inverse Agonist Screening

Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists

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