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更新于：2025-06-07

T-5224

更新于：2025-06-07

概要

概要

基本信息

药物类型

小分子化药

别名

R 7277、R-7277、T 5224

+ [1]

靶点

c-Fos x c-Jun

作用方式

抑制剂

作用机制

c-Fos抑制剂(Fos proto-oncogene, AP-1 transcription factor subunit inhibitors)、c-Jun抑制剂(Transcription factor Jun inhibitors)

治疗领域

免疫系统疾病皮肤和肌肉骨骼疾病

在研适应症-

非在研适应症

类风湿关节炎

原研机构

FUJIFILM Holdings Corp.

在研机构-

非在研机构

FUJIFILM Holdings Corp.Toyama Chemical Co., Ltd.

权益机构

Roche Holding AGToyama Chemical Co., Ltd.

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C29H27NO8

InChIKeyDALCQQSLNPLQFZ-UHFFFAOYSA-N

CAS号530141-72-1

关联

项与 T-5224 相关的临床试验

JPRN-jRCT2080221322

/ Unknown status临床2期

Phase IIa study of T-5224 in RA patients

开始日期2010-12-01

申办/合作机构

Toyama Chemical Co., Ltd.

100 项与 T-5224 相关的临床结果

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100 项与 T-5224 相关的转化医学

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100 项与 T-5224 相关的专利（医药）

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项与 T-5224 相关的文献（医药）

2025-06-19·ONCOGENE

A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer

Article

作者: Huang, Juyuan ; Cao, Jing ; Lyu, Qiongying ; Yang, Fan ; Zhang, Wei ; Fan, Guanlan ; Luo, Manwen ; Chen, Yurou ; Zhao, Qiuyan ; Xiong, Jie ; Xiong, Jiaqiang ; Liu, Yanyan ; Wang, Jingtao ; Li, Feng ; Xing, Yuzhu

Cancer stem cells (CSCs) are closely associated with drug resistance and recurrence in ovarian cancer patients. Although leptin is a high-risk factor for ovarian cancer and promotes stemness maintenance, a therapeutic strategy that counteracts the downstream signaling pathway of leptin remains elusive. Herein, the deubiquitinase OTUD1 was identified as a critical regulator of leptin in maintaining OCSCs properties. Mechanistically, leptin treatment significantly increased the chromatin enrichment of the transcription factor c-Jun, including the OTUD1 gene enhancer, which was sufficient to increase the OTUD1 protein level and subsequently cause OTUD1 aggresome formation, ASK1 recruitment and JNK/c-Jun pathway activation. The resultant positive feedback loop of c-Jun and OTUD1 was required for OCSCs stemness maintenance. Notably, the disruption of the positive feedback loop by targeting c-Jun or ASK1/JNK with T-5224, selonsertib, or ibrutinib markedly inhibited the leptin-induced stemness maintenance of OCSCs and tumorigenicity. Our findings reveal a crucial mechanism for leptin-mediated stemness maintenance and indicate that targeting c-Jun or the identified positive feedback loop has translational potential for ovarian cancer patients.

2025-05-01·Journal of Orthopaedic Translation

Single-cell transcriptomic analysis reveals AP-1 downregulation remodels bone marrow environment and contributes to osteopenia in ovariectomized mice

Article

作者: Zhou, Xuhui ; Zhang, Zheng ; Gao, Rui ; Tao, Zhengbo ; Tao, Xia ; Xu, Xunpei ; Zhang, Xuanrui ; Zhang, Zhanrong ; Zhang, Weijin

Background:

Estrogen deficiency-induced osteoporosis largely results from disrupted immune environment in bone marrow, yet the underlying cellular and molecular mechanisms remain incompletely understood. This study aimed to investigate how estrogen deficiency alters bone marrow cellular composition and signaling pathways, with a focus on the regulatory role of activator protein 1 (AP-1) and its impact on osteoclastogenesis.

Methods:

Single-cell RNA sequencing (scRNA-seq) was performed on bone marrow cells from sham-operated and ovariectomized (OVX) mice to map cell-type-specific changes. AP-1 inhibitor T5224 was administered to validate its functional role in vivo, while in vitro experiments assessed AP-1 activation via estrogen receptor signaling under estrogen stimulation. B lymphogenesis was pharmacologically inhibited using an IL-7 monoclonal antibody in OVX mice to evaluate its therapeutic potential.

Results:

OVX mice exhibited a marked expansion of proliferative B cells (enriched in protein translation/DNA replication pathways) and reduced neutrophil proportions. scRNA-seq revealed widespread downregulation of AP-1 subunits, namely Fos, Fosb, Jun, Junb, across multiple cell types. T5224-induced AP-1 inhibition recapitulated OVX-associated B cell/neutrophil imbalance and triggered significant bone loss. Mechanistically, estrogen receptor activation upregulated AP-1 under estrogen stimulation, whereas AP-1 inhibition promoted B cell proliferation and increased GM-CSF and RANKL levels, thereby facilitating osteoclastogenesis. Critically, IL-7 antibody-mediated suppression of B lymphogenesis in OVX mice substantially attenuated bone loss.

Conclusion:

AP-1 downregulation drives estrogen deficiency-related osteopenia by disrupting bone marrow homeostasis, primarily through excessive B cell expansion and elevated osteoclastogenic signaling. Targeting B cell proliferation via IL-7 blockade presents a potential therapeutic strategy for mitigating osteoporosis in estrogen-deficient conditions.

2025-03-12·Science Translational Medicine

Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models

Article

作者: Guo, Jason L. ; Delitto, Daniel ; Wan, Derrick C. ; Marshall, Clement D. ; Korah, Maria ; Berry, Charlotte E. ; Foster, Deshka S. ; Fallah, Mahsa ; Hyun, Jeong S. ; Longaker, Michael T. ; Griffin, Michelle ; Appel, Eric A. ; Song, Rachel ; Januszyk, Michael ; Wernig, Gerlinde ; Bauer-Rowe, Khristian Erich ; Meany, Emily ; Norton, Jeffrey A. ; Chinta, Malini S. ; Lopez, David M. ; Kim, Alexia ; Williams, Christian M.

Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.

项与 T-5224 相关的新闻（医药）

2025-04-01

·今日头条

微环境调控新视角：哈医大研究揭示乳腺癌精准治疗潜在路径

【导读】中性粒细胞胞外诱捕网（NETs）在癌症转移中发挥着重要作用。然而，NET 介导的三阴性乳腺癌（TNBC）肺转移的分子机制仍不清楚。 3月28日，哈尔滨医科大学研究团队在期刊《Journal of Experimental & Clinical Cancer Research》上发表了研究论文，题为“C-FOS promotes the formation of neutrophil extracellular traps and the recruitment of neutrophils in lung metastasis of triple-negative breast cancer”，本研究表明抑制 c-FOS 能够抑制三阴性乳腺癌（TNBC）的肿瘤生长和肺转移。从机制上讲，c-FOS 通过与 PAD4 启动子区域结合促进转录，从而促进中性粒细胞外网（NETs）的形成。此外，ROS-p38 通路的激活进一步增强了 c-FOS 的表达。c-FOS 的高表达还促进了炎症因子的表达，从而促进中性粒细胞的募集。体外和体内实验均表明，应用 T5224 能够有效抑制 NETs 的形成，从而抑制肺转移和肿瘤生长。 https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03370-2#Sec32 研究背景 01 乳腺癌是女性中最常见的恶性肿瘤，也是全球女性癌症相关死亡的第二大原因，对女性的健康和生命构成重大威胁。三阴性乳腺癌（TNBC）约占乳腺癌病例的 20%，其特点是生存率低、转移率高以及缺乏有效的治疗靶点，也被称为“最毒乳腺癌”。因此，进一步探究 TNBC 的转移机制，尤其是肿瘤微环境中的复杂相互作用，已成为当前研究的重点。中性粒细胞是血液中数量最多的白细胞类型，在人体免疫反应中发挥着重要作用。中性粒细胞能够形成由 DNA 链和相关蛋白水解酶组成的中性粒细胞胞外陷阱（NETs），主要用于捕获和消灭病原体。然而，转移性乳腺癌细胞能够诱导中性粒细胞形成 NETs，从而支持肿瘤转移。 T5224靶向c-FOS治疗可有效控制TNBC的进展和中性粒细胞浸润 02 研究人员旨在评估靶向c-FOS 的治疗是否能有效抑制乳腺癌的发展。首先，研究人员利用 4T1 细胞构建三阴性乳腺癌原位肿瘤模型，并通过腹腔注射给予抑制剂。结果表明，T5224 和 DNase I 治疗均能有效减缓肿瘤生长。研究人员发现，在预先用 PMA 处理的模型中，T5224 的治疗效果更佳。免疫组化染色显示，预先用 PMA 处理的小鼠中 Ly6G 的阳性率显著降低。这一趋势也在组织 MPO、CitH3 和 c-FOS 的免疫荧光染色结果中得到体现。接下来，研究人员通过尾静脉注射 4T1 细胞构建三阴性乳腺癌肺转移模型，并用 T5224 进行治疗。研究发现，单独使用 T5224 以及在 PMA 预处理后使用 T5224 均能有效减轻乳腺癌肺转移。与对照组相比，治疗组转移性肿瘤中 Ly6G、MPO、CitH3 和 c-FOS 的阳性率显著降低。最后，为了阐明 c-FOS 靶向治疗在肿瘤生长和肺转移中的机制，研究人员评估了肿瘤的增殖能力、血管密度和细胞凋亡情况。结果表明，c-FOS 靶向治疗有效降低了肿瘤中 Ki67 的阳性率，抑制了血管生成，并增强了肿瘤细胞凋亡。此外，在肺转移性肿瘤中也观察到了类似的趋势。总之，这些数据证实了 c-FOS 对肿瘤相关中性粒细胞的调节作用，这表明 c-FOS 可能是乳腺癌肺转移的治疗靶点。靶向 c-FOS 治疗能够抑制肿瘤生长和肺部转移结论 03 总之，本研究表明，c-FOS 可通过 ROS-p38-cFOS-PAD4 通路促进三阴性乳腺癌（TNBC）中NETs的形成。该通路还促进 MIP-1α 和 IL-1ra 以及其他炎症因子的表达，从而促进中性粒细胞募集，形成预转移微环境。靶向c-FOS 的治疗可改善肿瘤微环境，从而抑制肿瘤生长和肺转移，但仍需进一步研究和临床试验。因此，靶向 c-FOS/NETs 通路的研究为发现 TNBC 的免疫治疗靶点提供了理论参考。参考资料： https://jeccr.biomedcentral.com/articles/10.1186/s13046-025-03370-2#Sec32 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。责任声明：本稿件如有错误之处，敬请联系转化医学网客服进行修改事宜！微信号：zhuanhuayixue 热门推荐活动点击免费报名 🕓 线上｜2025年4月2日19:00-21:00 ▶ 大咖领衔，共话携筛 | 基因科技开拓携带者筛查新纪元 🕓 上海｜2025年6月12-15日 ▶ 第七届上海国际癌症大会暨中国生物工程学会医学生物技术专业委员会年会暨第六届中德双边论坛 🕓 北京｜2025年09月19-20日 ▶ 第六届单细胞技术应用研讨会暨空间组学前沿研讨会点击对应文字查看详情

临床研究临床结果

100 项与 T-5224 相关的药物交易

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