更新于：2024-11-01

信号转导蛋白

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与信号转导蛋白相关的药物

hM4Di-DREADD

靶点

信号转导蛋白

作用机制

信号转导蛋白抑制剂

在研机构

The Ohio State University Wexner Medical Center [+1]

原研机构

Cincinnati Children's Hospital Medical Center

在研适应症

脊髓损伤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

Erucylphosphocholine

靶点

信号转导蛋白

作用机制

信号转导蛋白抑制剂

在研机构-

原研机构

Æterna Zentaris, Inc.

在研适应症-

非在研适应症

肿瘤

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

CPC-300

靶点

RAS x 信号转导蛋白

作用机制

RAS 调节剂 [+1]

在研机构-

原研机构

DMK Pharmaceuticals Corp.

在研适应症-

非在研适应症

胰腺癌 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与信号转导蛋白相关的临床结果

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100 项与信号转导蛋白相关的转化医学

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0 项与信号转导蛋白相关的专利（医药）

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项与信号转导蛋白相关的文献（医药）

2022-01-15·Oncotarget

Suppressive GLI2 fragment enhances liver metastasis in colorectal cancer

Article

作者: Goto, Kei ; Luo, Yi ; Sasaki, Takamitsu ; Mori, Shiori ; Nishiguchi, Yukiko ; Kishi, Shingo ; Ohmori, Hitoshi ; Kawahara, Isao ; Kuniyasu, Hiroki ; Nakashima, Chie ; Ogata, Ruiko ; Fujiwara-Tani, Rina

Linoleic acid (LA) has been shown to cause inflammation and promote development of colorectal cancer (CRC). Moreover, many literatures show that LA is associated with cancer metastasis. Metastatic cancer cells have high stemness, suggesting that LA might affect the stemness of cancer cells. In this study, we examined the effect of LA on the hedgehog system, which affects cancer stemness. In CT26 cells, LA treatment induced the expression of sonic hedgehog (Shh); the signal transduction factor, and glioma-associated oncogene homolog (Gli) 2, whereas the expression of SRY-box transcription factor (Sox) 17 was suppressed. Furthermore, LA reduced GLI2 ubiquitination, resulting in an increase in the N-terminal fragment of GLI2, known as suppressive GLI2, produced by cleavage of GLI2. LA-induced cleaved GLI2 was also detected in Colo320 and HT29 human CRC cells. Knocking down Gli2 abrogated the LA-mediated suppression of Sox17 expression. These results suggest that LA promotes tumor cell stemness by increasing of suppressive GLI2 fragments via GLI2 modification. In mouse liver metastasis models, LA enhanced metastasis with production of the suppressive GLI2 fragments in CT26 and HT29 cells, whereas knockdown of GLI2 abrogated LA-induced metastatic activity. In human CRCs, the cases with liver metastasis showed the suppressive GLI2 fragments. This study provides mechanistic insights into LA-induced stemness in colon cancer cells. This finding suggests that dietary intake of LA might increase the stemness of cancer cells and enhance metastatic activity of the cancer.

2021-03-01·Genome Biology and Evolution2区 · 生物学

Divergence in Coding Sequence and Expression of Different Functional Categories of Immune Genes between Two Wild Rodent Species

2区 · 生物学

ArticleOA

作者: Lundberg, Max ; Råberg, Lars ; Zhong, Xiuqin

AbstractDifferences in immune function between species could be a result of interspecific divergence in coding sequence and/or expression of immune genes. Here, we investigate how the degree of divergence in coding sequence and expression differs between functional categories of immune genes, and if differences between categories occur independently of other factors (expression level, pleiotropy). To this end, we compared spleen transcriptomes of wild-caught yellow-necked mice and bank voles. Immune genes expressed in the spleen were divided into four categories depending on the function of the encoded protein: pattern recognition receptors (PRR); signal transduction proteins; transcription factors; and cyto- and chemokines and their receptors. Genes encoding PRR and cyto-/chemokines had higher sequence divergence than genes encoding signal transduction proteins and transcription factors, even when controlling for potentially confounding factors. Genes encoding PRR also had higher expression divergence than genes encoding signal transduction proteins and transcription factors. There was a positive correlation between expression divergence and coding sequence divergence, in particular for PRR genes. We propose that this is a result of that divergence in PRR coding sequence leads to divergence in PRR expression through positive feedback of PRR ligand binding on PRR expression. When controlling for sequence divergence, expression divergence of PRR genes did not differ from other categories. Taken together, the results indicate that coding sequence divergence of PRR genes is a major cause of differences in immune function between species.

2020-12-01·Journal of Cellular Physiology2区 · 生物学

Glial cell line‐derived neurotrophic factor alters lipid composition and protein distribution in MPP+‐injured differentiated SH‐SY5Y cells

2区 · 生物学

Article

作者: Sun, Shen ; Gao, Dianshuai ; Liu, Yuting ; Gao, Jin ; Li, Li ; Jiang, Shimin ; Mu, Peipei

AbstractParkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and striatum. Glial cell line‐derived neurotrophic factor (GDNF) can effectively promote the differentiation and survival of many types of neurons, especially dopaminergic neurons, suggesting it could be a treatment for PD. Lipid rafts are highly dynamic cell membrane domains that contain numerous signal protein receptors, providing an important platform for signal transduction. Compelling evidence indicates that alterations in lipid rafts are associated with PD, and some studies have reported that GDNF can regulate the expression of caveolin‐1, a lipid raft‐marker protein. However, the precise effects of GDNF on lipid rafts remain unknown. We developed a cellular PD model, purified detergent‐resistant membranes (membrane rafts), and performed proteomic and lipid metabolomics analyses to examine changes in lipid rafts after GDNF treatment. The results showed considerable protein and lipid alterations in response to GDNF, especially altered levels of dopamine‐β‐hydroxylase, heat shock 70 kDa protein, neural cell adhesion molecule, cytoskeletal proteins, and long‐chain polysaturated/unsaturated fatty acids. These findings reveal a new avenue to explore the relationships between GDNF, lipid rafts, and PD and support the hypothesis that GDNF may be a useful treatment for PD.

项与信号转导蛋白相关的新闻（医药）

2023-04-20

·CPHI制药在线

市场 | 默沙东斥资百亿美元收购Prometheus，IBD市场格局如何？

关注并星标CPHI制药在线4月16日，默沙东（MSD）和生物技术公司Prometheus Biosciences共同宣布，默沙东计划以108亿美元现金为代价收购Prometheus，该交易预计将于2023年第三季度完成。 Prometheus成立于2016年，是一家处于临床阶段的生物技术公司。通过此次收购，默沙东将获得Prometheus的领先候选药物PRA023，这是一种针对肿瘤坏死因子（TNF）类配体1A（TL1A）的人源化单克隆抗体（mAb）。 PRA023在治疗溃疡性结肠炎与克罗恩病的两项II期临床试验中，结果显示：在治疗中重度溃疡性结肠炎的随机双盲II期临床试验中，在治疗12周后，PRA023组中有26.5%的患者达到临床缓解的主要终点，对照组为1.5%，这一临床缓解率高于目前市面上治疗溃疡性结肠炎的常用药物，具有BIC潜力；36.8%的患者达到内镜改善的次要终点，对照组为6%。在治疗中重度活动性克罗恩病（CD）患者的开放标签IIa期APOLLO-CD临床试验中，共招募55例中重度活动性CD并伴有内窥镜活动性疾病且常规或生物治疗失败的患者。结果显示：PRA023组有26%的患者获得内镜缓解，对照组为12%。 TL1A单抗在炎症性肠病（IBD）的研发进展 TL1A属TNF超家族成员，是一种2型跨膜蛋白，主要由内皮细胞表达。TL1A通过与其受体DR3结合，从而激活下游信号，参与先天性和适应性免疫稳态。炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD），是一种慢性全身炎症性自免疾病，其特征是肠道炎症、组织损伤、腹痛、频繁/持续性腹泻、体重减轻、直肠出血、疲劳等。TL1A通过介导炎症和纤维化，在IBD治疗中发挥重要作用。除了PRA023，目前进入临床II期的TL1A单抗还有辉瑞的PF 6480605（RVT-3101）和梯瓦制药的TEV-48574。 PF 6480605在一项IIa期TUSCANY研究中对50 例中重度UC患者进行了评估，其中42例受试者完成了研究。结果显示，在治疗的第14周，内窥镜改善率为 38.2%；最常见的不良事件是UC疾病加重和关节疼痛。 TEV-48574于2022年8月完成II期临床RELIEVE UCCD 研究首例受试者的入组工作，拟开发适应症为克罗恩病和溃疡性结肠炎，研究计划招募280例受试者，预计于2024年10月完成。其他IBD药物市场布局作为免疫介导的系统性疾病，IBD的主要治疗方式是药物治疗，其主要治疗药物包括氨基水杨酸、皮质类固醇激素、免疫抑制剂、抗生素、生物制剂五大类。其中生物制剂是IBD治疗的主流药物，目前获批上市的生物制剂有英夫利西单抗、阿达木单抗、乌司奴单抗和维得利珠单抗。阿达木单抗由艾伯维研发，是一款肿瘤坏死因子（TNF）拮抗剂，通过与TNF-α特异性结合，来阻止TNF-α激活p55和p75细胞表面的TNF受体。其批准的适应症包括溃疡性结肠炎、类风湿关节炎等。乌司奴单抗是一种全人源IgG1k单克隆抗体，可结合 IL-12/23的p40亚单位，于2020年3月，乌司奴单抗在我国获批克罗恩病适应症，用于对传统治疗或TNFα拮抗剂应答不足或无法耐受的成年中重度活动性克罗恩病患者。维得利珠单抗是一款靶向整合素α4β7单抗，被批准用于治疗对传统治疗手段或TNFα治疗疗效不足或已经耐受的成人中重度UC和CD等适应症。可与表达在记忆T淋巴细胞表面的α4β7整合素特异性结合，阻断α4β7整合素与粘膜地址素细胞粘附分子-1（MAdCAM-1）相互作用，抑制记忆T淋巴细胞迁移至肠道的炎症组织，从而减少肠道黏膜炎症。除生物制剂外，小分子抑制剂在UC和CD治疗中也扮演了重要角色。Janus激酶（JAK）分子激活信号转导蛋白和转录活化因子（STAT）DNA结合蛋白是参与UC和CD病理学的主要细胞因子，因此抑制JAK-STAT通路已成为新型IBD治疗的一个潜力靶点。乌帕替尼（Upadacitinib）是由艾伯维研发的一款选择性和可逆性JAK抑制剂。2019年，乌帕替尼获FDA批准，用于治疗对甲氨蝶呤反应不足或不耐受的中重度活动性类风湿关节炎成人患者。2022年3月，FDA批准乌帕替尼扩展适应症，用于治疗中重度活动性溃疡性结肠炎成人患者，这类患者对一种或多种TNF阻断剂反应不足或不耐受。在临床试验中，乌帕替尼在治疗8周和52周时达到临床缓解的主要终点。同时更多接受乌帕替尼治疗的患者获得临床应答，并且在第8周和第52周时达到关键性内镜和组织学改善终点。除了JAK抑制剂外，IBD治疗领域的小分子抑制剂还有S1P受体调节剂Zeposia，这是一款口服的1-磷酸鞘氨醇受体调节剂，与S1P受体1和5具有高亲和力。Zeposia减少了淋巴细胞从淋巴结排出的能力，减少了外周血中循环淋巴细胞的数量。目前，研究者普遍认为Zeposia治疗UC的作用机制可能与减少淋巴细胞向炎症肠粘膜的迁移有关。当前，全世界约有1260万人患有IBD，除了减少引发病症的炎症，降低并发症的风险，目前还没有治愈IBD的方法。根据Global Data给出的CD市场规模预测，预计到2026年，CD药物治疗市场将达到134亿美元。目前炎症性肠病领域仍然存在着严重的未满足临床需求，未来谁主沉浮？我们持续关注。参考来源： 1. RINVOQ® (upadacitinib) Receives FDA Approval for the Treatment of Adults with Moderately to Severely Active Ulcerative Colitis. Retrieved March 16, 2022, from https://www.prnewswire.com/news-releases/rinvoq-upadacitinib-receives-fda-approval-for-the-treatment-of-adults-with-moderately-to-severely-active-ulcerative-colitis-301504545.html. 2. Chaparro M, Baston-Rey I, Fernández-Salgado E, et. al Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients: The SUSTAIN Study. Inflamm Bowel Dis. 2022 Nov 2;28(11):1725-1736. doi: 10.1093/ibd/izab357. PMID: 35166347; PMCID: PMC9629456. 3. 张国兴, 石荣. 溃疡性结肠炎治疗进展[J]. 现代中西医结合杂志,2019,28(25):2842-2847. 4. 吴全峰, 赵立波, 王晓玲, 等. 炎症性肠病的治疗药物研究进展[J]. 中国药师, 2020,23(10):2011-2019. 5. Zhang Y,et al. Long-term trends in the burden of inflammatory bowel disease in China over three decades: A joinpoint regression and age-period-cohort analysis based on GBD 2019. Front Public Health. 2022 Sep 7;10:994619. 智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

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