A Phase II, Multicenter, Double-blind, Randomized, Placebo-controlled, Clinical study Evaluating the Efficacy, Safety and Tolerability of a Targeted Single Injection of an Intradiscal AMG0103 in Subjects with Chronic Discogenic Lumber Back Pain

开始日期2023-06-19

申办/合作机构-

NCT03263611 / Completed临床1期

A Phase 1b, Multicenter, Double-blind, Randomized, Placebo-controlled, Single Ascending-Dose, Clinical Study Evaluating the Safety, Tolerability and Exploratory Efficacy of a Targeted Single Injection of an Intradiscal Nuclear Factor-κB Decoy Oligodeoxynucleotide (AMG0103) in Subjects With Chronic Discogenic Lumbar Back Pain

This clinical trial evaluate the safety, tolerability and exploratory efficacy of targeted single injection of AMG0103 in subject with chronic discogenic lumbar back pain

开始日期2018-02-26

申办/合作机构

AnGes, Inc.

NCT01443065 / Completed临床2期IIT

MEGA (Met or EGFR Inhibition in Gastroesophageal Adenocarcinoma): FOLFOX Alone or in Combination With AMG 102 or Panitumumab as First-line Treatment in Patients With Advanced Gastroesophageal Adenocarcinoma FNCLCC-FFCD-AGEO PRODIGE 17-ACCORD 20 Randomized Phase II Trial

This multicentre, open-label, randomized phase II trial is ongoing in 30 centres in France. Main eligibility criteria include: histologically proven adenocarcinoma of the stomach, esophagus or gastroesophageal junction; locally advanced or metastatic disease; measurable disease (RECIST 1.1); no known HER2 overexpression; no prior palliative chemotherapy.

开始日期2011-01-01

申办/合作机构

UNICANCER

100 项与 Cupabimod 相关的临床结果

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100 项与 Cupabimod 相关的转化医学

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100 项与 Cupabimod 相关的专利（医药）

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项与 Cupabimod 相关的文献（医药）

2024-02-01·Bioorganic chemistry

Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma

Article

作者: Xiong, Xiao-Feng ; Liu, Lu ; Ye, Jia ; Fan, Guangjin ; Xiao, Wei

Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding Gαq and Gα11 proteins are key genes to drive UM, making the selective inhibition of Gαq/11 proteins to be a potential therapeutic approach for combating UM. In this study, forty-six quinazoline derivatives were designed, synthesized, and assessed for their ability to inhibit Gαq/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against Gαq/11 proteins (IC₅₀ = 9.4 μM) and two UM cell lines MP41 (IC₅₀ = 6.7 μM) and 92.1 (IC₅₀ = 3.7 μM). Being a small molecule inhibitor of Gαq/11 proteins, F33 could effectively suppress the activation of downstream signaling pathways in a dose-dependent manner, and significantly inhibits UM in vitro.F33 represents a promising lead compound for developing therapeutics for UM by targeting Gαq/11 proteins.

2023-12-01·Cancer biotherapy & radiopharmaceuticals

Screening and Preclinical Evaluation of Novel Radiolabeled Anti-Fibroblast Activation Protein-α Recombinant Antibodies

Article

作者: Geng, Changran ; Xu, Shasha ; Luo, Zhigang ; Tang, Xiaobin ; Xu, Jianfeng ; Li, Shenghua ; Wang, Zheng ; Cui, Jingjing ; Cai, Fei ; Dai, Juan

Background: Fibroblast activation protein-α (FAPα) is selectively overexpressed in tumor-associated fibroblasts in more than 90% of epithelial tumors, and may be a good target for anticancer treatment, for example, using an anti-FAPα recombinant antibody (rAb) labeled with radionuclides. In the present report, the radiolabeling and preclinical evaluation of novel anti-FAPα rAbs were investigated. Materials and Methods: Two novel anti-FAPα VHHs (AMS002-1 and AMS002-2) with high binding affinity to FAPα were selected from an antibody phage library. The anti-FAPα VHHs were then fused with the Fc fragment of human IgG4 to create two VHH-Fc rAbs. The VHH-Fc rAbs were radiolabeled with ⁸⁹Zr and ¹⁷⁷Lu. The radiolabeled products were evaluated by radioligand-binding assays using FAPα-expressing cells. The biodistribution and tumor-targeting properties were investigated by small-animal PET/CT. AMS002-1-Fc, which showed promising tumor-targeting properties in ⁸⁹Zr-microPET imaging, was radiolabeled with ¹⁷⁷Lu for efficacy study on HT1080 tumor-bearing mice and monitored with SPECT/CT imaging. Results: The two VHH-Fc rAbs with good affinity with K_D values in low nanomolar range were identified. Both PET/CT imaging with ⁸⁹Zr-AMS002-1-Fc rAb and SPECT/CT imaging with ¹⁷⁷Lu-AMS002-1-Fc rAb demonstrated highest tumor uptakes at 72 h p.i. and long tumor retention in the preclinical models. Furthermore, ex vivo biodistribution analysis revealed high tumor uptake of ⁸⁹Zr-AMS002-1-Fc at 48 h p.i. with the value of 6.91% ± 2.08% ID/g. Finally, radioimmunotherapy with ¹⁷⁷Lu-AMS002-1-Fc rAb delayed the tumor growth without significant weight loss in mice with HT1080 xenografts. The tumor size of untreated control group was 2.59 times larger compared with the treatment group with ¹⁷⁷Lu-AMS002-1-Fc at day 29. Conclusion: ⁸⁹Zr/¹⁷⁷Lu-AMS002-1-Fc represent a pair of promising radiopharmaceuticals for theranostics on FAPα-expressing tumors.

2023-02-01·Melanoma research

Orthotopic murine xenograft model of uveal melanoma with spontaneous liver metastasis

Article

作者: Lorenzo, Daniel ; Vinyals, Antònia ; Ramos, Raquel ; Paules, Maria José ; Fabra, Àngels ; Caminal, José M. ; Gomá, Montse ; Ferreres, Josep R. ; Piulats, Josep M. ; Cabré, Eduard ; Gutierrez, Cristina ; Varela, Mar

Uveal melanoma is the most common intraocular malignancy in adults. Despite the effective primary treatment, up to 50% of patients with uveal melanoma will develop metastatic lesions mainly in the liver, which are resistant to conventional chemotherapy and lead to patient’s death. To date, no orthotopic murine models of uveal melanoma which can develop spontaneous metastasis are available for preclinical studies. Here, we describe a spontaneous metastatic model of uveal melanoma based on the orthotopic injection of human uveal melanoma cells into the suprachoroidal space of immunodeficient NSG mice. All mice injected with bioluminescent OMM2.5 (n = 23) or MP41 (n = 19) cells developed a primary tumor. After eye enucleation, additional bioluminescence signals were detected in the lungs and in the liver. At necropsy, histopathological studies confirmed the presence of lung metastases in 100% of the mice. Liver metastases were assessed in 87 and in 100% of the mice that received OMM2.5 or MP41 cells, respectively. All tumors and metastatic lesions expressed melanoma markers and the signaling molecules insulin-like growth factor type I receptor and myristoylated alanine-rich C-kinase substrate, commonly activated in uveal melanoma. The novelty of this orthotopic mouse xenograft model is the development of spontaneous metastases in the liver from the primary site, reproducing the organoespecificity of metastasis observed in uveal melanoma patients. The faster growth and the high metastatic incidence may be attributed at least in part, to the severe immunodeficiency of NSG mice. This model may be useful for preclinical testing of targeted therapies with potential uveal melanoma antimetastatic activity and to study the mechanisms involved in liver metastasis.

项与 Cupabimod 相关的新闻（医药）

2024-01-29

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超低分子量化合物库如何增大在化学空间的覆盖率

寻找苗头化合物如大海捞针为给定靶点找到苗头化合物跟大海捞针无异，其中有四个关键因素影响新药靶点的发现：（假设至少存在一个小分子结合口袋）用于筛选的化合物库的化学空间覆盖范围新靶点上的结合口袋与历史药物靶点上的口袋的相似性用于筛选的检测技术的灵敏度（和信噪比）以剂量依赖的方式确认特定靶点与预期靶点结合的能力因此，如何以更少量的分子实现更大范围的化学空间覆盖率就是一个亟待解决的现实问题。由于化学空间的规模过于巨大，寻找新药物靶点的苗头化合物在药物发现过程非常困难。GDB-17数据库2005年，Jean-Louis Reymond等人建立了GDB-11数据库，GDB-11按照简单的化学稳定性和合成可行性规则，列举了最多含 11 个C、N、O 和 F原子的小分子有机物，整个数据库拥有 2640 万个结构。5年之后，他们建立了GDB-13。GDB-13扩大到最多含 13 个 C、N、O、S 和 Cl 原子的小分子有机物，共拥有 977 468 314 个结构。2012年他们继续扩大规模建立了GDB-17。这是一个包含17个重原子（C、N、O、S和卤素）的1664亿分子库。这样，我们就可以估算出 17 个重原子以内的化学空间大小。在GDB-17中每增加一个重原子，化学空间就平均增加5倍，这里用于估计超过17个重原子的化学空间的大小（该数据不包括立体异构体）。从上面推导的 GDB-17 累积化学空间大小的数字中，我们可以得出每个重原子数下有化学意义的分子的预期数量（见下图）。例如，奥希替尼的重原子数为 37，其化学空间大小为 1.3×1025。随着药物规模的扩大，化学空间也会急剧增加。以埃维罗莫斯（Everolimus）为例，其的重原子数为 68，化学空间为 6×1046 。化学空间覆盖率如果能够针对所有蛋白质筛选所有可能的化合物，就有可能为所有可药物靶点找到药物分子。在没有包含所有可能化合物的化合物筛选库的情况下，一般化合物库的主要目标是最大限度地覆盖化学空间。化学空间覆盖率是待筛选化合物库中化合物总数与整个化学空间的比值。相对化学空间覆盖率是给定化合物库在给定分子大小下覆盖的化学空间百分比（通常使用重原子数）。基于片段的筛选通过使用重原子数较少的分子化合物库（称为片段）来最大化化学空间覆盖率，因为这些分子的相对化学空间仍然相对较小，因此更容易覆盖。基于片段的药物发现由 Steve Fesik 于 1996 年首创，将片段库与灵敏的检测方法相结合，以识别目标蛋白靶点的苗头化合物。让我们看一下典型片段库和典型高通量筛选库之间相对化学空间覆盖率的比较。片段库中化合物的平均大小为 15 个重原子，而 HTS 库中化合物的平均大小则翻了一番，约为 30 个重物原子。从15个重原子增加到30个重原子，GDB-17估计的化学空间增加了100亿倍（相当于 10 个数量级）。为了便于计算，我们假设我们的片段库由一千种化合物组成，而我们的 HTS 库有一百万种化合物。即使库中的化合物数量减少了一千倍，我们的片段库覆盖相对化学空间的效率也要高 1000 万倍。显然，化学库中的化合物大小各不相同，化学功能的组成也各不相同，但面对化合物大小增加后相对化学空间覆盖率的巨大差异，这种影响可能微乎其微。建立小型化合物的大型数据库Astex 的同事们将这一概念发挥到了极致，推出了所谓的 minifrag library（超低分子量化合物库 - 重原子数 5-7）。一个由 80 个平均重原子数为 6.4 的 minifrags 组成的化合物库，与由平均重原子数为 10.6 的 440 个化合物组成的较大（但仍然很小）的 X 射线筛选集相比，命中率明显提高。与 Xray 筛选集 0.004% 到 0.03% 的覆盖率相比，minifrag 库的相对化学空间覆盖率在 1% 到 7% 之间。这样看来像Minifrag library这样建立小型化合物的大型数据库是一个可以高效提高化学空间覆盖率的方法。图 1. MiniFrag 统计数据。(a) 用于 X 射线筛选的 MiniFrag 和历史 X 射线集的平均性质。N 是每组中配体的数量，HAC 是非氢重原子的平均数量，MW 是平均分子量（Da），clogP 是正辛醇与水之间分配系数的计算对数。PSA 是计算得出的极性表面积。NDon、NAcc 和 Nrot 分别是氢键供体、氢键受体和可旋转键的数量。Fsp3 是 sp3 杂化碳的比例。(b) MiniFrag 和历史 X 射线集筛选的输出。苗头化合物定义为至少与目标蛋白质结合一次的 MiniFrag。标有 * 的靶点是使用包含 352 个片段的历史 X 射线集筛选的，而不是其余靶点使用的 440 个片段。PPI-2 是一个小 GTPase 靶点。对于所有靶点，MiniFrags 的命中率远远高于 X 射线集（MiniFrag 和 X 射线集的平均命中率分别为 44% 和 12%）。所有靶点的命中率差异在统计学上都非常显著（P < 0.00003），但需要注意的是，由于实验参数的微小差异，这种命中率的相互比较并不完全严格。MiniFrag 筛选（所有靶点）共鉴定出 68 个独特的苗头化合物和 316 个总靶点。(c) 通过 MiniFrags（蓝柱）或 X 射线集（红柱）筛选确定的地点数量。一个地点被定义为包含两个或两个以上从统一的筛选结果集得出的空间重叠命中点的地点。灰条显示的是为每个目标识别出的非空间重叠、唯一位点的总和。在所有情况下，MiniFrags 都能识别出更多的可用地点，但也有 MiniFrags 未能检测到 X 射线集筛选中突出显示的地点的情况（从上文的维恩图中可以看出）。维恩图指的是筛选出的五个靶点，并显示了仅由 MiniFrags 识别、仅由 X 射线集识别以及由 MiniFrags 和 X 射线集采样的地点数量。参考资料：https://mcconnellsmedchem.com/2024/01/09/chemical-space-is-big/O’Reilly M, Cleasby A, Davies T G, et al. Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design[J]. Drug discovery today, 2019, 24(5): 1081-1086.版权信息本文系AIDD Pro接受的外部投稿，文中所述观点仅代表作者本人观点，不代表AIDD Pro平台，如您发现发布内容有任何版权侵扰或者其他信息错误解读，请及时联系AIDD Pro (请添加微信号sixiali_fox59)进行删改处理。本文为原创内容，未经授权禁止转载，授权后转载亦需注明出处。有问题可发邮件至sixiali@stonewise.cn关注我，更多资讯早知道↓↓↓

100 项与 Cupabimod 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05559

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
特应性皮炎	临床3期	-	Nippon Zoki Pharmaceutical Co. Ltd.	-
特应性皮炎	临床3期	-	AnGes, Inc.	-
特应性皮炎	临床3期	-	Osaka University	-
特应性皮炎	临床3期	-	Shionogi & Co., Ltd.	-
椎间盘退化	临床1期	美国	AnGes, Inc.	2018-02-26
腰痛	临床1期	美国	AnGes, Inc.	2018-02-26