Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development
Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun
Hongmin Wu, Xiancai Zhong, Ning Ma, Zhiheng He, Guanpeng Wang, Geming Lu, Yate-Ching Yuan, Wencan Zhang, Yun Shi, Nagarajan Vaidehi, Evelyn Peelen, Tanja Wulff, Christian Gege, Hella Kohlhof, Daniel Vitt, Yousang Gwack, Ichiro Taniuchi, Hai-Hui Xue, Zuoming Sun
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Research Article Autoimmunity Immunology

Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development

Abstract

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.

Authors

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

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Figure 1

IMU-935 potently inhibits IL-17 production from human PBMCs.

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IMU-935 potently inhibits IL-17 production from human PBMCs. (A) Chemica...
(A) Chemical structure of IMU-935. (B) A dose-response curve for IMU-935–inhibited RORγt luciferase reporter activity in the INDIGO assay in the presence of different concentrations of IMU-935 (n = 2 technical replicates per point). (C and D) A dose-response curve for IMU-935–inhibited IL-17A (C) or IL-17F (D) production from phytohaemagglutinin-stimulated human PBMCs for 2 days and measured by Luminex. Data shown are from 1 representative donor (n = 3 technical replicates per point). Summary data from the 4 donors are shown in Supplemental Figure 1A. (E) Cocrystal structure of RORγt and IMU-935. Left: A crystal structure of IMU-935 (yellow sticks) complexed with the RORγt LBD. The IMU-935 binding site is accentuated by a red circle, and the IMU-935 binding pocket’s morphological contours are delineated by a blue surface. Top right: An enhanced close-up representation reveals the spatial orientation of IMU-935 (yellow sticks) and its interactions with neighboring structures and amino acids (blue sticks). Lower right: A superimposition of IMU-935 with compound-1 (Cpd-1) is depicted in the binding pocket of RORγt. The distance between IMU-935 or Cpd-1 and the X-loop (indicated in magenta) located between H1 and H2 is illustrated by dashed lines.