AS2863619 is an orally administered small molecule inhibitor of cyclin-dependent kinase (CDK) 8 and 19 with IC50 of 0.6099nM and 4.277nM, respectively. AS2863619 inhibits serine phosphorylation in the PSP motifs of signal transducer and activator of transcription 5 (STAT5) and somehow enhances phosphorylation of tyrosine residues in the C-terminal domain, leading to enhanced activation of STAT5 and thus activation of various STAT5-binding genes, including Treg signature genes such as Forkhead box p3 (Foxp3) and CD25 [1-2]. AS2863619 converts naïve and effector/memory antigen-specific CD4+ and CD8+ T cells into Foxp3+ Tregs in vitro through an IL-2-dependent but TGF-β-independent mechanism[3]. AS2863619 is useful in promoting the differentiation and proliferation of erythroid progenitor cells or erythroid precursor cells[4].
In vitro, healthy human T cells were cultured following anti-CD3/CD28 activation with AS2863619 and observed significant increases in T cell expansion, confirming that the kinase module restrains T cell expansion CDK19[5]. Cochlear explants from C57BL/6J were cultured for a day and treated with cisplatin for another day; over half of the OHCs were lost. In the basal region, both AS2863619 (1μmol/L or 5μmol/L) and ribociclib co-treatments effectively alleviated the cisplatin-induced damage of OHCs[6].
In vivo, in a skin contact hypersensitivity model (sensitization with 2,4-dinitrofluorobenzene (DNFB)), mice were orally administered AS2863619 (30mg/kg) daily for 2 weeks. This treatment dampened the degree of the secondary response in a Treg cell-dependent manner, with milder infiltration of inflammatory cells into the skin and decreased ratios of interferon-γ+ (IFN-γ+) cells in the regional lymph nodes when compared with vehicle-treated control mice[2, 7].
References:
[1] Wang L, Wang Y, Liu C, et al. Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment. Mater Today Bio. 2023;19:100557.
[2] Akamatsu M, Mikami N, Ohkura N, et al. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci Immunol. 2019;4(40):eaaw2707.
[3] Bonam SR, Bayry J. For antigen-specific effector or Foxp3+ regulatory T cell fate, cyclin-dependent kinases hold the trump card. Cell Mol Immunol. 2020;17(4):310-312.
[4] Gu Y, Wu L, Gao H, et al. Use of RO8191 and AS2863619 in promoting differentiation and proliferation of erythroid progenitor cells or erythroid precursor cells. Derwent Innovations Index. 2023;2023-913047.
[5] Freitas KA, Belk JA, Sotillo E, et al. Enhanced T cell effector activity by targeting the Mediator kinase module. Science. 2022;378(6620):eabn5647.
[6] Zheng L, Shen Q, Zhao T, et al. A Novel Functional Method of Protector Screening for Zebrafish Lateral Line Hair Cells via the Acoustic Escape Response. Neurosci Bull. Published online May 6, 2025.
[7] Cully M. Treg conversion dampens autoimmunity. Nat Rev Drug Discov. 2019;18(12):903.
AS2863619是一种口服小分子环依赖性激酶（CDK）8和19抑制剂，IC50值分别为0.6099nM和4.277nM。AS2863619可抑制信号转导子和转录激活子5（STAT5）中PSP基序的丝氨酸磷酸化，同时在某种程度上增强了C端结构域酪氨酸残基的磷酸化，从而增强了STAT5的激活作用，并激活包括Treg标志性基因（如Forkhead box p3（Foxp3）和CD25）在内的多种STAT5结合基因[1]。AS2863619可通过一种依赖IL-2但不依赖TGF-β的机制，将初始型和效应/记忆型抗原特异性CD4+和CD8+ T细胞在体外转化为Foxp3+调节性T细胞（Tregs）[3]。此外，AS2863619在促进红系祖细胞或红系前体细胞的分化和增殖方面也具有一定应用价值[4]。
在体外，将健康人T细胞经过抗CD3/CD28激活后与AS2863619共同培养，观察到T细胞扩增显著增加，证实CDK19激酶模块在抑制T细胞扩增方面起作用[5]。从C57BL/6J小鼠获得的耳蜗外植体培养一天后再给予顺铂处理一天，结果表明超过一半的外毛细胞（OHCs）丢失。在耳蜗基底区，1μmol/L或5μmol/L的AS2863619与ribociclib联用，均能有效缓解顺铂引起的OHC损伤[6]。
在体内，在皮肤接触超敏模型（以2,4-二硝基氟苯（DNFB）致敏）中，小鼠每日口服给予30mg/kg的AS2863619，持续两周。该处理在Treg细胞依赖性机制下减弱了二次免疫反应，与对照组相比，炎症细胞在皮肤中的浸润程度较低，区域淋巴结中干扰素-γ+（IFN-γ+）细胞比例也显著下降[2, 7]。