Author: Taniuchi, Ichiro ; Kohlhof, Hella ; Xue, Hai-Hui ; Lu, Geming ; Ma, Ning ; Gwack, Yousang ; Peelen, Evelyn ; Vaidehi, Nagarajan ; Gege, Christian ; Vitt, Daniel ; Sun, Zuoming ; He, Zhiheng ; Shi, Yun ; Yuan, Yate-Ching ; Wulff, Tanja ; Wang, Guanpeng ; Zhong, Xiancai ; Zhang, Wencan ; Wu, Hongmin

RORγt is a key transcription factor regulating both Th17 differentiation and thymocyte development. Although Th17 cells drive autoimmune diseases, inhibiting RORγt to treat autoimmunity also disrupts thymocyte development and can cause lethal thymic lymphoma. We identified a previously unreported RORγt cofactor, CBFβ, and a highly selective RORγt inhibitor, IMU-935, that preferentially disrupt the RORγt-CBFβ interaction in Th17 cells but not thymocytes. This interaction is essential for RORγt function; mice with a RORγt mutant unable to bind CBFβ had impaired Th17 differentiation, were resistant to experimental autoimmune encephalomyelitis (EAE), and had defective thymocyte development. IMU-935 inhibited Th17 differentiation and reduced EAE severity without affecting thymocyte development by selectively targeting the RORγt-CBFβ interaction in Th17 cells but not in thymocytes. This differential effect arose because different concentrations of IMU-935 were required to disrupt the interaction in Th17 cells versus thymocytes, due to varying levels of RUNX1 that compete with RORγt for CBFβ binding. This study reveals an unreported mechanism for RORγt regulation and a selective RORγt inhibitor that prevents Th17-driven autoimmunity without the risk of lethal lymphoma from thymocyte disruption.

01 Dec 2021·Respiratory researchQ2 · MEDICINE

RORγt inhibitors block both IL-17 and IL-22 conferring a potential advantage over anti-IL-17 alone to treat severe asthma

Q2 · MEDICINE

ArticleOA

Author: Erjefält, Jonas S ; De Sousa, Dorothy ; Hoffmann, Hans Jürgen ; Lamb, David ; Delic, Denis ; Schmid, Ramona ; Fundel-Clemens, Katrin ; Kästle, Marc ; Sandén, Caroline ; Menden, Kevin ; Quast, Karsten

Abstract:

Background:

RORγt is a transcription factor that enables elaboration of Th17-associated cytokines (including IL-17 and IL-22) and is proposed as a pharmacological target for severe asthma.

Methods:

IL-17 immunohistochemistry was performed in severe asthma bronchial biopsies (specificity confirmed with in situ hybridization). Primary human small airway epithelial cells in air liquid interface and primary bronchial smooth muscle cells were stimulated with recombinant human IL-17 and/or IL-22 and pro-inflammatory cytokines measured. Balb/c mice were challenged intratracheally with IL-17 and/or IL-22 and airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured. Balb/c mice were sensitized intraperitoneally and challenged intratracheally with house dust mite extract and the effect of either a RORγt inhibitor (BIX119) or an anti-IL-11 antibody assessed on airway hyperreactivity, pro-inflammatory cytokines and airway neutrophilia measured.

Results:

We confirmed in severe asthma bronchial biopsies both the presence of IL-17-positive lymphocytes and that an IL-17 transcriptome profile in a severe asthma patient sub-population. Both IL-17 and IL-22 stimulated the release of pro-inflammatory cytokine and chemokine release from primary human lung cells and in mice. Furthermore, IL-22 in combination with IL-17, but neither alone, elicits airway hyperresponsiveness (AHR) in naïve mice. A RORγt inhibitor specifically blocked both IL-17 and IL-22, AHR and neutrophilia in a mouse house dust mite model unlike other registered or advanced pipeline modes of action. Full efficacy versus these parameters was associated with 90% inhibition of IL-17 and 50% inhibition of IL-22. In contrast, anti-IL-17 also blocked IL-17, but not IL-22, AHR or neutrophilia. Moreover, the deregulated genes in the lungs from these mice correlated well with deregulated genes from severe asthma biopsies suggesting that this model recapitulates significant severe asthma-relevant biology. Furthermore, these genes were reversed upon RORγt inhibition in the HDM model. Cell deconvolution suggested that the responsible cells were corticosteroid insensitive γδ-T-cells.

Conclusion:

These data strongly suggest that both IL-17 and IL-22 are required for Th2-low endotype associated biology and that a RORγt inhibitor may provide improved clinical benefit in a severe asthma sub-population of patients by blocking both IL-17 and IL-22 biology compared with blocking IL-17 alone.

01 Sep 2019·Fitoterapia

Discovery of betulinaldehyde as a natural RORγt agonist

Article

Author: Ni, Dongxuan ; Luo, Xiaomin ; Xiao, Weilie ; Zhang, Ruihan ; Yang, Feng ; Luo, Cheng ; Chen, Shijie

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a dual-functional therapeutic target. The agonists and inhibitors of RORγt are potential agents for tumor immunotherapy and autoimmune diseases, respectively, and sometimes share similar scaffolds. Although the widely distributed triterpenoid ursolic acid (UA) has been identified as a RORγt inhibitor, the report of a triterpenoid RORγt agonist is still absent. By screening an in-house triterpenoid library, we uncovered a novel RORγt agonist, betulinaldehyde (1), together with an inhibitor (2, 3β, 28-Dihydroxy-lupan-29-oic acid). Compound 1 showed a good RORγt activating effect with the EC₅₀ of 11.4 μM in Alpha Screen assay, and altered the thermal stability of RORγt by directly binding to the protein in vitro. Combined with the SPR assay, the Kd value of compound 1 was examined as 2.99 μM. The modulation mechanism of triterpenoid agonists and inhibitors were discussed by molecular docking. Herein, we firstly discovered compound 1 as a triterpenoid agonist of RORγt. The co-distribution of triterpenoid RORγt agonist and inhibitors in the same plant, might be related to the anti-inflammatory and anti-cancerous bioactivity of the plant extract.

100 Deals associated with RORγt Inhibitor (Impetis Biosciences)

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Indication	Highest Phase	Country/Location	Organization	Date
Castration-Resistant Prostatic Cancer	Preclinical	India	Impetis Biosciences Ltd.	30 Nov 2022
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