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A novel CDK8/19 inhibitor RO8323 mitigates allograft rejection through dual mechanisms of action to modulate regulatory T cell and myeloid cell

Acta Pharmacologica Sinica (2026) Cite this article

Abstract

Regulatory T (Treg) cells are pivotal in maintaining immune homeostasis through suppression of effector T (Teff) cells, making their therapeutic modulation a promising strategy for treating autoimmune and inflammatory diseases. CDK8/19 inhibitors promote Treg cell differentiation by upregulating Foxp3 expression in both naive and memory/effector T cells. In this study we identified a novel dual CDK8/19 inhibitor RO8323 and systematically dissected the mechanism of CDK8/19-mediated immunoregulation. RO8323 inhibited CDK8 and CDK19 with IC50 values of 2 nM and 3 nM, respectively, displaying >100-fold kinome selectivity. In the in vitro and in vivo experimental settings, we demonstrated that RO8323 selectively enhanced Treg differentiation while suppressing Teff. Furthermore, RO8323 exerted anti-inflammatory effects on myeloid cells by selectively upregulating IL-10 production but not proinflammatory cytokines (TNF-α, IL-6, and IL-12) following TLR agonist activation. In the DBA/2 → BALB/c cGVHD model, administration of RO8323 (3 mg·kg−1·d−1, i.g.) from day 7 to day 49 displayed significant therapeutic potential by reducing clinical severity scores and enhancing immune reconstitution —a finding reported for the first time in this context. Complementary studies using an ear-heart transplantation model revealed that administration of RO8323 (3, 10 mg·kg−1·d−1, i.g.) dose-dependently prolonged cardiac allograft survival accompanied by increased Treg frequencies. These results not only elucidate the immunomodulatory mechanisms of CDK8/19 inhibition but also highlight its translational value for managing alloimmune responses such as GVHD and transplant rejection.

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Fig. 1: CDK8/19 kinase inhibition promotes Treg differentiation and suppresses effector T cells in vitro and in vivo.
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Fig. 2: Transcriptomic profiling reveals that CDK8/19 inhibition downregulates IFN pathways and Th1/Th17 signature genes in activated CD4+ T cells in vitro.
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Fig. 3: CDK8/19 kinase inhibition potentiates IL-10 production in TLR-stimulated immune cells in vitro and in vivo.
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Fig. 4: Pharmacological CDK8/19 inhibition prevents cGVHD and attenuates renal pathology in mice.
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Fig. 5: CDK8/19 inhibition increases Treg populations and enhances immune reconstitution in cGVHD mice.
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Fig. 6: Pharmacological inhibition of CDK8/19 prolongs cardiac allograft survival in mice.
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Acknowledgements

The authors gratefully acknowledge Lu Qian, Shi-ying Lin, Yun-liang Wu, Jian-quan Wu, and Cui-ting Zhang for their essential contributions to in vitro and in vivo experiments. We thank Dr. Gijs van Brink for his expert scientific consultation and Roche colleagues for their dedicated project support. We appreciate Labcorp and PharmaLegacy Laboratories for their partnership in conducting animal studies. This research was funded by F. Hoffmann-La Roche A.G.

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Authors and Affiliations

  1. China Innovation Center of Roche, Shanghai, 201203, China

    Fang Shen, Rou Xie, Ye Gan, Ping Ren, Ran-ran Wu, Jia-wei Yan, Yu-ying Bian, Cheng-cheng Liu, Song Yang, Xin-chun Han, Chen-gang Zhou, Yao Wu, Yang Tang, Zhi-heng Xu, Jun Yang, Hong-xia Qiu, Ju-hao Yang, Xue-yan Pu, Li Li, Yue Gui, Gu-liang Xia, Hong C. Shen, Hao-chu Huang & Lue Dai

  2. Pharmaceutical Research and Early Development, F. Hoffmann-La Roche AG, Roche Innovation Center Basel, Basel, 4070, Switzerland

    Kara G. Lassen

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  1. Fang Shen
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Contributions

This study was conceptualized by GLX, LD, KGL, HCH, HCS, FS; FS, PR, RRW, RX, YG designed, executed, and analyzed experiments; JWY, YYB, and CCL assisted with bioinformatic analyses; SY, XCH, CGZ, YT, JY, ZHX, YW, HXQ, JHY, LL, YG, XYP performed the chemical synthesis and related analysis; all authors reviewed data, discussed conclusion and assisted in manuscript preparation; FS and LD, wrote the manuscript with input from all authors. GLX and KGL revised the manuscript.

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Shen, F., Xie, R., Gan, Y. et al. A novel CDK8/19 inhibitor RO8323 mitigates allograft rejection through dual mechanisms of action to modulate regulatory T cell and myeloid cell. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-026-01773-1

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