A Single-center, Single- and Multiple-Dose Phase 1 Study to Evaluate the Safety and Pharmacokinetics of TAK-114 in Healthy Adult Japanese and Caucasian Male Subjects

The purpose of this study is to evaluate the safety and tolerability of TAK-114 following single and multiple ascending oral doses in healthy Japanese male participants.

开始日期2014-11-01

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

JPRN-jRCT2080222640 / Unknown status临床1期

A Single-center, Single- and Multiple-Dose Phase 1 Study to Evaluate the Safety and Pharmacokinetics of TAK-114 in Healthy Adult Japanese and Caucasian Male Subjects

开始日期2014-10-28

申办/合作机构

Takeda Pharmaceutical Co., Ltd.

NCT01216280 / Unknown status临床2期

Efficacy and Tolerability Study of Natura-Alpha in the Treatment of Patients With Active Ulcerative Colitis

This study is to evaluate the efficacy and tolerability of multiple oral doses of Natura-alpha capsule administered to patients with active ulcerative colitis. This will be a randomized, double-blind, placebo-controlled, parallel-design study. Up to 75 patients will complete this study (20 to 25 patients per treatment group) at approximately 10-12 clinical sites in the Unites States. Patients will be assigned at a 1:1:1 ratio to receive placebo, Natura-alpha 10 mg or Natura-alpha 20 mg, b.i.d. Replacement patients may be added, pending Sponsor approval, if it appears that less than 60 patients will complete the study.

开始日期2010-07-01

申办/合作机构

Natrogen Therapeutics International, Inc.

100 项与甲异靛相关的临床结果

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100 项与甲异靛相关的转化医学

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100 项与甲异靛相关的专利（医药）

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项与甲异靛相关的文献（医药）

2024-07-01·European Journal of Medicinal Chemistry

Discovery of meisoindigo derivatives as noncovalent and orally available Mpro inhibitors: their therapeutic implications in the treatment of COVID-19

Article

作者: Zhou, Yuzheng ; Xia, Zanxian ; Fan, Jinbao ; Ke, Shufen ; Wang, Yuxuan ; Liu, Sixu ; Fan, Kaiqiang ; Deng, Xu ; Zhou, Yingjun ; Gao, Qingtian ; Zhou, Yuqing

The progressive emergence of SARS-CoV-2 variants has necessitated the urgent exploration of novel therapeutic strategies to combat the COVID-19 pandemic. The SARS-CoV-2 main protease (M^pro) represents an evolutionarily conserved therapeutic target for drug discovery. This study highlights the discovery of meisoindigo (Mei), derived from the traditional Chinese medicine (TCM) Indigo naturalis, as a novel non-covalent and nonpeptidic M^pro inhibitor. Substantial optimizations and structure-activity relationship (SAR) studies, guided by a structure-based drug design approach, led to the identification of several Mei derivatives, including S5-27 and S5-28, exhibiting low micromolar inhibition against SARS-CoV-2 M^pro with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC₅₀ up to 2.66 μM. Furthermore, it displayed favorable physiochemical properties and remarkable gastrointestinal and metabolic stability, demonstrating its potential as an orally bioavailable drug for anti-COVID-19 therapy. This research presents a promising avenue for the development of new antiviral agents, offering hope in the ongoing battle against COVID-19.

2024-05-09·Journal of Medicinal Chemistry

Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors

Article

作者: Yan, Linyang ; Fan, Jinbao ; Wang, Qing ; Xia, Zanxian ; Zhou, Yingjun ; Zhou, Yuxing ; Ye, Baixin ; Liu, Tingting ; Xu, Jiahao ; Liu, Ting-Ting ; Deng, Xu

Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC 9b was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that 9b potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. 9b-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for anti-cancer therapy. Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

2023-04-01·Toxicology

In silico, in vitro and in vivo studies: Dibutyl phthalate promotes prostate cancer cell proliferation by activating Forkhead Box M1 and remission after Natura-α pretreatment

Article

作者: Liu, Bianjiang ; Zhou, Xiang ; Miao, Chenkui ; Tang, Sensheng ; Bu, Hengtao ; Yang, Haiwei ; Liu, Guiting

Dibutyl phthalate (DBP) is widely used in perfumes, cosmetics, shampoos and medical devices. It is ubiquitous in the environment and greatly endangers people's health. Several studies have reported that being exposed to it can promote the development of lung cancer, breast cancer, hepatoma, and multiple myeloma. However, there are still few studies on the specific molecular mechanism and prevention methods of DBP promoting the progression of prostate cancer. This study, in silico, in vitro and in vivo, aims to explore the promoting effect of DBP on prostate cancer cell proliferation. In silico analysis, we obtained a set of DBP interactive genes by utilizing TCGA, CTD and GEO database. These genes are mainly enriched in cell cycle regulatory pathways and they have high degree of homogeneity. We found that these genes shared one transcription factor - Forkhead Box M1 (FOXM1) by performing Chip-X Enrichment Analysis (Version 3.0). FOXM1, once called the 2010 Molecule of the Year, aberrantly expressed in up to 20 kinds of tumors. In vitro experiments, we used DBP at concentrations of 10^-8 M and 5 * 10^-7 M to treat C4-2 and PC3 cells for 6 days, respectively. Cell viability was promoted significantly. When Natura-α was added in the background of above-mentioned concentration of DBP, this effect was significantly inhibited. In addition, we also found that DBP can interfering with the efficacy of enzalutamide therapy. The introduction of Natura-α can also reverse this phenomenon. In vivo, subcutaneous tumor formation experiments in nude mice, 800 mg/kg/day DBP can promote the growth of prostate cancer. This phenomenon was suppressed when Natura-α (100 mg/kg/day) was added. Based on the results of the above three levels, we confirmed that DBP can target FOXM1 to promote prostate cancer cell proliferation. Natura-α can reverse its cancer-promoting effect. This study provides new insights into the impact of DBP on prostate cancer.

项与甲异靛相关的新闻（医药）

2024-04-25

·精准药物

【JMC】中南大学邓旭教授等报道新型ATM降解剂

2024年4月18日，中南大学湘雅药学院邓旭教授以“Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors”为题在线发表在药物化学领域国际顶级期刊Journal of Medicinal Chemistry上。作者基于定量蛋白质组学策略，成功设计并合成第一个高效和选择性ATM降解剂Mei-PROTAC 9b。9b单独暴露或联合ATR抑制剂诱导DNA损伤累积和凋亡细胞死亡，在体外和体内均显示出优异的抗结直肠活性。其研究结果不仅为靶向DDR的结直肠癌治疗提供了新的范式，而且通过合成致死作用拓宽了ATR抑制剂的治疗范围，从而为规避化疗耐药和减少耐药的出现提供了一种有前景的方法。靶向DNA损伤应答(DDR)通路内的关键细胞周期检查点，如共济失调毛细血管扩张突变(ATM)和共济失调毛细血管扩张和RAD3相关(ATR)，是一种有前景的癌症精准治疗策略。ATM和ATR属于磷脂酰肌醇3-激酶相关蛋白激酶家族，通过响应特定的DNA损伤因素来协调DDR。ATM和DNA依赖性蛋白激酶主要对双链DNA断裂(DSBs)产生应答，而ATR在复制应激期间被单链DNA损伤激活，例如某些遗传毒性药物(如顺铂)治疗后DNA复制叉出现停滞。具体而言，DSB上ATM的激活导致关键下游转导子和效应子的磷酸化，包括DSB修复因子CtIP、组蛋白变异体H2AX、肿瘤抑制因子BRCA1和p53以及检查点转导激酶CHK2，从而导致细胞周期阻滞和促进DDR过程。尽管ATM通路的破坏具有显著意义，但高达70%的肿瘤中观察到这些缺陷导致细胞生存依赖于代偿性DDR途径(即ATR-CHK1轴)。因此，选择性地抑制ATR活性可在ATM缺乏的情况下诱导合成致死，这为克服化疗耐药和提高疗效提供了一种有前景的策略。Mei通过抑制多种致癌途径，包括DNA生物合成、微管组装和细胞周期阻滞等对多种恶性肿瘤有抑制作用，包括急性髓系白血病(AML)和急性早幼粒细胞白血病(APL)，结直肠和胰腺导管腺癌等。然而，Mei抑制癌细胞生长的确切机制以及直接分子靶点仍不清楚。为探究甲异靛(Mei)在慢性髓性白血病(CML)治疗中的分子靶点和作用机制，作者设计和合成一系列Mei-PROTACs。Mei-PROTACs对不同癌细胞的抑制作用图1 (A) 9b对多种癌细胞的抑制作用；(B) 不同浓度9b处理SW620、SW480和HIEC-6细胞的细胞活力作者通过系列化合物的合成，分别得到CRBN型和VHL型的Mei-PROTACs，其中VHL型的PROTACs比CRBN型的PROTACs具有更优异的肿瘤抑制作用。这可能是由于蛋白质表面特性的变化，使得VHL能够建立稳定的三元复合物和高亲和力结合界面。随后，作者进一步测试了9b和6f对一系列癌细胞的细胞毒性。如表1和图1A所示，9b表现出对多种癌细胞的低微摩尔细胞毒性。SW620细胞和SW480细胞对9b的敏感性显著高于亲本化合物Mei和VH032-Boc。此外，9b对结直肠癌细胞的选择性是正常人肠上皮细胞HIEC-6的6倍且呈剂量依赖性(图1B)。对应的，6f对除A2780、SW620和RKO细胞外的大多数癌细胞株的增殖无明显影响。鉴于其显著的细胞毒性，优化后的PROTAC 9b成为后续研究结直肠癌细胞系(SW620和SW480细胞)中药物作用靶点和机制的焦点。9b诱导的ATM降解高度依赖vhl介导的泛素-蛋白酶体途径9b在SW620和SW480中以时间和浓度依赖性的方式有效降解ATM（图2A, B）。为了进一步评估9b诱导ATM降解的VHL-蛋白酶体依赖机制，作者进行了一系列的验证，包括:(1)与相应的E3泛素连接酶配体和母体化合物的竞争实验;(2)在蛋白酶体抑制剂和溶酶体抑制剂存在的情况下进行9b处理。结果表明：在SW620和SW480细胞中，VHL配体VH032-Boc和亲本化合物Mei可以剂量依赖性地拮抗9b诱导的ATM降解。这些结果表明，9b介导的ATM降解是通过Mei部分与ATM和VH032部分与VHL结合形成VHL-9b-ATM三元复合物来实现的。此外，选择性蛋白酶体抑制剂MG132和Epoxomicin(图2F、G)共处理可终止9b诱导的ATM降解。图2：9b对ATM的降解作用9b与ATR抑制剂AZD6738联用可有效抑制小鼠体内的肿瘤生长为了进一步验证9b的治疗效果，并进一步证实ATM和ATR抑制在结直肠癌中合成致死的概念，作者在SW620异种移植小鼠模型上评估了9b的体内抗肿瘤活性，剂量为15 mg kg -1 (9b)和/或25 mg kg -1 (AZD6738)，每天1次，连续14天(每组n = 5)。如图3A、B所示，与空白对照组、9b或AZD6738单药治疗相比，9b和AZD6738联合治疗显著降低了肿瘤负荷，显示出协同作用，证明了在体内ATM降解和ATR抑制之间存在的合成致死效应。此外，如图3C所示，在给予9b, AZD6738或其组合方案后，小鼠的体重没有明显下降，表明其具有良好的耐受性。通过对切除的肿瘤标本进行切片、HE染色，以及随后的免疫组织化学形态学分析，探讨体内肿瘤细胞的形态学变化和凋亡诱导。如图3D所示，9b和AZD6738治疗刺激了显著的形态学变化，并伴有坏死、炎症细胞浸润和纤维化的征象。此外，9b/AZD6738组合显著增强了γ-H2AX(表明DNA损伤)和Cleavedcaspase 3(细胞凋亡的标志)的免疫反应性(图3D)。图3：9b和ATR抑制剂在异种移植小鼠模型中的体内治疗作用总结为探究甲异靛(Mei)在慢性髓性白血病(CML)治疗中的分子靶点和作用机制，作者设计和合成一系列Mei-PROTACs。VHL型PROTAC分子 9b对SW620、SW480和K562细胞具有较高的细胞毒性。结合广泛的验证分析，揭示了9b在SW620和SW480细胞中以泛素-蛋白酶体依赖的方式有效和选择性地降解ATM。9b诱导的ATM选择性降解促进了DNA损伤反应级联反应，从而导致细胞周期阻滞和细胞凋亡。值得注意的是，在体内外实验中，9b诱导的ATM降解协同增强了ATR抑制剂AZD6738的作用。这项工作确定了ATR抑制剂在ATM缺乏的情况下的合成致死性，从而为结直肠癌的创新疗法提供了新途径。原文链接： https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00454声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体临床结果

100 项与甲异靛相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	L01XX	-

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
肿瘤	中国	北京协和药厂有限公司	2001-01-01

未上市

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适应症	最高研发状态	国家/地区	公司	日期
溃疡性结肠炎	临床2期	美国	Takeda Pharmaceuticals International AG	-
溃疡性结肠炎	临床2期	欧盟	Takeda Pharmaceuticals International AG	-
前列腺癌	临床2期	美国	Natrogen Therapeutics International, Inc.	-
系统性红斑狼疮	临床2期	美国	Natrogen Therapeutics International, Inc.	-
活动性重度溃疡性结肠炎	临床前	美国	Natrogen Therapeutics International, Inc.	2010-07-01