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

Wang, Yonghui; Yang, Ting; Liu, Qian; Ma, Yingli; Yang, Liuqing; Zhou, Ling; Xiang, Zhijun; Cheng, Ziqiang; Lu, Sijie; Orband‐Miller, Lisa A.; Zhang, Wei; Wu, Qianqian; Zhang, Kathleen; Li, Yang; Xiang, Jia‐Ning; Elliott, John D.; Leung, Stewart; Ren, Feng; Lin, Xichen

doi:10.1016/j.bmc.2015.07.068

Cited by 32 publications

(19 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The FRET and dual FRET assays were performed as previously described . The assay buffer consisted of 50 m m NaF, 50 m m 3‐( N ‐morpholino)propanesulfonic acid, pH 7.4, 0.05 m m 3‐[(3‐cholamidopropyl)dimethylammonio]propanesulfonate, 0.1 mg/mL BSA, and 10 m m dithiothreitol.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

Gabr

Abdel-Raziq

2018

Chemistry & Biodiversity

View full text Add to dashboard Cite

A new series of fluorene derivatives was designed and synthesized as novel retinoic acid receptor-related orphan receptor gamma t (RORγt) inverse agonists utilizing a molecular hybridization approach. The new compounds 10 - 15 were evaluated for their RORγt activity using biochemical FRET and cellular reporter gene assays. Moreover, the inhibitory activity of the fluorene derivatives 10 - 15 in mouse Th17 cell differentiation assay was assessed. The hybrid compound 15 that combines both fluorene and arylsulfone moieties displayed promising RORγt activity with IC values of 68.6 and 99.5 nm in FRET and cellular assays, respectively. In addition, molecular modeling studies were employed to investigate potential binding mode of 15 to RORγt. These results render 15 a potential lead compound for development of therapeutics for Th17-driven autoimmune diseases.

show abstract

Section: Methodsmentioning

confidence: 99%

“…The FRET and dual FRET assays were performed as previously described. [32] The assay buffer consisted of 50 mM NaF, Reporter Gene Assay. The reporter gene assay was performed using human Jurkat cells, Clone E6-1 (ATCC) using previosly described procedure.…”

Section: Biological Assaysmentioning

confidence: 99%

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

Gabr

Abdel-Raziq

2018

Chemistry & Biodiversity

View full text Add to dashboard Cite

show abstract

“…By this successful discovery of a small molecule inverse agonist of RORγt and its biological efficacy, RORγt attracted much attention as a promising pharmacological target for inflammatory diseases. So far many pharmaceutical companies and institutions have reported various inverse agonists of RORγt [23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist

et al. 2018

View full text Add to dashboard Cite

Background/Aims: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. Methods: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. Results: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORβ. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. Conclusion: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.

show abstract

“… Overlay of reported compounds (PDB IDs: 3L0L, 4XT9, 4YMQ and 5APJ) and fragment hits bound in the LBP of RORγt. Color coding: cartoon representation of the secondary structures and the pocket shape as light grey; published compounds (A–C), 3l0l white carbons, 4xt9 green, 4ymq cyan, 5apj orange; all fragment hits (D–F) as grey models except CT6 light pink, CT16 pink, CT23 yellow, CT24 blue.…”

Section: Figurementioning

confidence: 99%

“…To illustrate the ligand bindingm odes and the pocket shape, complex structures with knownR ORgtl igandsw ere used for comparison. Structures with PDB codes 3L0L, [16] 4XT9, [17] 4YMQ [18] and 5APJ [13] (lowerc ase letters of the PDB codes indicate the respective ligandsinthe structures)were included for superposition (Figure3A-C, G). In comparison, the fragment hits identified in the current study were shown in Figure 3D-F.I ti se vident that the fragment hits were able to probe the entire space of the LBP,a nd showed discrete hotspots (designated as site-1 through site-5 in subsequent description, see .…”

mentioning

confidence: 99%

Fragment Screening of RORγt Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments

2016

View full text Add to dashboard Cite

The retinoic-acid-related orphan receptor γ t (RORγt), as a master regulator of Th17 cell pathology, has become an attractive target for small-molecule drug discovery for the treatment of Th17-cell-related autoimmune diseases. A crystallographic fragment screening was carried out for RORγt using the ligand binding domain. An overall hit rate of 5.5 % was obtained by screening 384 compounds in 96 cocktails. Five distinct hotspots were identified, and four regions of anchoring polar interactions were observed. In addition, significant induced fit was found for the binding of several fragments. Strikingly, a simultaneous binding of three fragments was revealed which presents interesting features including π-π stacking, multiple hydrogen bonds to the protein, and significant induced fit. Overall, the results offer a complete mapping of the ligand binding pocket and provide valuable inspiration in structure-based design for RORγt lead generation and optimization. The crystallographic screening also resulted in fragment hits that bind at the surface away from the ligand binding pocket. This surface site is near the plausible dimer interface by analogy with other nuclear receptor systems, which can provide initial hints to explore alternative ways to modulate RORγt through protein-protein interactions.

show abstract

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

Cited by 32 publications

References 35 publications

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

Structure‐Based Design and Synthesis of Fluorene Derivatives as Novel RORγt Inverse Agonists

Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist

Fragment Screening of RORγt Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments

Contact Info

Product

Resources

About