compound 4(英矽智能)(Compound 4) - 药物靶点：PTP1B x PTPN2_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

化学药

别名-

靶点

PTP1B x PTPN2

作用机制

PTP1B抑制剂(蛋白酪氨酸磷酸酶-1B抑制剂)、PTPN2 抑制剂(蛋白酪氨酸磷酸酶非受体2型抑制剂)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

英矽智能(香港)有限公司初创企业

在研机构

英矽智能(香港)有限公司初创企业

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)临床前

特殊审评-

关联

100 项与 compound 4(英矽智能) 相关的临床结果

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100 项与 compound 4(英矽智能) 相关的转化医学

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100 项与 compound 4(英矽智能) 相关的专利（医药）

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50

项与 compound 4(英矽智能) 相关的文献（医药）

2025-01-01·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

To explore the mechanism of gypenosides in the treatment of liver injury in rats based on GC-MS metabolomics and bile acid metabolism pathway

Review

作者: Chen, Yu ; Yue, Rong ; Zhang, Zhiru ; Wang, Miao ; Wang, Yibo ; Ma, Lizhou

Gynostemma pentaphyllum is a herbaceous vine of Cucurbitaceae family, and its principal pharmacological components, gypenosides (GPs), have been proved to be effective in various liver diseases. However, the mechanisms of GPs on liver injury are still to be studied for further. This investigation utilized the CCl₄-induced liver injury rat model (LI) to comprehensively explore the mechanism of action of GPs in the treatment of chemical liver injury by comparing the metabolomic changes in four groups rats. In this study, the therapeutic efficacy of GPs in a liver injury rat model induced by weekly gavage of CCl₄ was evaluated by inflammatory factors, oxidative damage indexes, and histopathological sections. Then, GC-MS technology was used to identify the metabolic profile of GPs in treating liver injury. Finally, the content variation of metabolites (BAs and SCFAs) was measured to elucidate the mechanism of GPs in the treatment of CCl₄-induced liver injury. After 8 weeks of administration, GPs effectively reduced the degree of LI and appeared a substantial tendency of reversing in the levels of MDA, GSH, CYP7E1, CYP7A1 and CYP27A1. Untargeted metabolomics suggested that GPs may play a role in BAs and SCFAs metabolism. Targeted metabolomics and ELISA confirmed the key role of GPs in increasing SCFAs levels and regulating BAs metabolism. Overall, this study indicated that GPs can alleviate CCl₄-induced liver injury. And GPs may exert beneficial effects on LI by affecting their metabolites (SCFAs and BAs).

2024-12-01·Toxicology reports

Peripheral serum iTRAQ-based proteomic characteristics of carbon tetrachloride-induced acute liver injury in Macaca fascicularis

Article

作者: Dongmei, Chen ; Shuangxing, Li ; Wei, Li ; Yufa, Miao ; Xingchao, Geng ; Li, Sun

Carbon tetrachloride (CCl₄) is a potent chemical compound that can induce liver cells necrosis. The purpose of this study was to evaluate the hepatic toxicity of CCl₄ exposure in Macaca fascicularis to explore the liver toxicity mechanism using a proteomic approach. One animal (no.F6) was intoxicated by oral gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil), and was sacrificed at 48 h after CCl₄ administration. Another blank control animal (no.F4) was sacrificed at the same time. The liver cells of the blank control animal showed normal hepatocyte morphology. However, the hepatocytes at 48 h time point after CCl₄ administration showed necrosis and vacuolation histopathologically. The animal No.F7∼F12 and no.M7∼M12 were administrated by gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil). Blood samples were collected before gavage administration, and served as the 0 h blank control samples. Then, blood samples were collected at 2 h, 48 h, 72 h and 168 h after CCl₄ exposure, and served as the test samples. Routine biochemistry and immunical parameters were performed using biochemistry analyzer for all serum. Then the serum from male and female animals at 0 h, 2 h, 48 h, and 72 h was mixed, respectively. The peripheral serum proteins at 0 h, 2 h, 48 h, and 72 h were extracted, then the proteins were enzymatically hydrolyzed and the peptides were isotopic labeled by isobaric tags for relative and absolute quantification (iTRAQ). Finally, the UniProt Protein Sequence Library of Macaca fascicularis was queried to identify and compare the differential proteins between different time points. The results showed that, as traditional biomarkers of liver injury, alanine aminotransferases (ALT) and aspartate aminotransferases (AST) showed a typical time-effect curve. Compared with 0 h, there were totally 55, 323, and 158 differential proteins (P value <0.05, Ratio fold >1.5, FDR<0.05) at 2 h, 48 h and 72 h, respectively. GO enrichment analysis of differentially expressed proteins only at 48 h involved 3 cellular components (P adjust value <0.05), and differential proteins at other time points had no significant enrichment. Furthermore, KEGG enrichment analysis showed that the toxicity effect of CCl₄ at different time points after administration was mediated through 22 pathways such as biosynthesis of antibiotics, carbon metabolism, biosynthesis of amino acids, peroxisome, cysteine and methionine metabolism, arginine biosynthesis, and complement and coagulation cascades (P adjust value <0.05). Among them, the counts of signaling pathway involved biosynthesis of antibiotics, carbon metabolism and biosynthesis of amino acids were more than 10 and the three pathways may play a greater role in toxicity progress after administration of CCl₄. PPI network analysis showed that there were 3, 52, and 13 nodes in the interaction of differential proteins at 2 h, 48 h, and 72 h, respectively. In conclusion, many differential proteins in peripheral blood were detected after CCl₄ administration, and the GO and KEGG enrichment analysis showed the toxicological mechanisms of CCl₄-induced liver injury and potential protection reaction mechanism for CCl₄ detoxication may be related with multi biological processes, signaling pathway and targets.

2024-12-01·Toxicology reports

Peripheral serum iTRAQ-based proteomic characteristics of carbon tetrachloride-induced acute liver injury in Macaca fascicularis

Article

作者: Shuangxing, Li ; Dongmei, Chen ; Wei, Li ; Yufa, Miao ; Xingchao, Geng ; Li, Sun

Carbon tetrachloride (CCl₄) is a potent chemical compound that can induce liver cells necrosis. The purpose of this study was to evaluate the hepatic toxicity of CCl₄ exposure in Macaca fascicularis to explore the liver toxicity mechanism using a proteomic approach. One animal (no.F6) was intoxicated by oral gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil), and was sacrificed at 48 h after CCl₄ administration. Another blank control animal (no.F4) was sacrificed at the same time. The liver cells of the blank control animal showed normal hepatocyte morphology. However, the hepatocytes at 48 h time point after CCl₄ administration showed necrosis and vacuolation histopathologically. The animal No.F7∼F12 and no.M7∼M12 were administrated by gavage with 15 % CCl₄ solution (10 mL/kg, dissolved in edible peanut oil). Blood samples were collected before gavage administration, and served as the 0 h blank control samples. Then, blood samples were collected at 2 h, 48 h, 72 h and 168 h after CCl₄ exposure, and served as the test samples. Routine biochemistry and immunical parameters were performed using biochemistry analyzer for all serum. Then the serum from male and female animals at 0 h, 2 h, 48 h, and 72 h was mixed, respectively. The peripheral serum proteins at 0 h, 2 h, 48 h, and 72 h were extracted, then the proteins were enzymatically hydrolyzed and the peptides were isotopic labeled by isobaric tags for relative and absolute quantification (iTRAQ). Finally, the UniProt Protein Sequence Library of Macaca fascicularis was queried to identify and compare the differential proteins between different time points. The results showed that, as traditional biomarkers of liver injury, alanine aminotransferases (ALT) and aspartate aminotransferases (AST) showed a typical time-effect curve. Compared with 0 h, there were totally 55, 323, and 158 differential proteins (P value <0.05, Ratio fold >1.5, FDR<0.05) at 2 h, 48 h and 72 h, respectively. GO enrichment analysis of differentially expressed proteins only at 48 h involved 3 cellular components (P adjust value <0.05), and differential proteins at other time points had no significant enrichment. Furthermore, KEGG enrichment analysis showed that the toxicity effect of CCl₄ at different time points after administration was mediated through 22 pathways such as biosynthesis of antibiotics, carbon metabolism, biosynthesis of amino acids, peroxisome, cysteine and methionine metabolism, arginine biosynthesis, and complement and coagulation cascades (P adjust value <0.05). Among them, the counts of signaling pathway involved biosynthesis of antibiotics, carbon metabolism and biosynthesis of amino acids were more than 10 and the three pathways may play a greater role in toxicity progress after administration of CCl₄. PPI network analysis showed that there were 3, 52, and 13 nodes in the interaction of differential proteins at 2 h, 48 h, and 72 h, respectively. In conclusion, many differential proteins in peripheral blood were detected after CCl₄ administration, and the GO and KEGG enrichment analysis showed the toxicological mechanisms of CCl₄-induced liver injury and potential protection reaction mechanism for CCl₄ detoxication may be related with multi biological processes, signaling pathway and targets.

2

项与 compound 4(英矽智能) 相关的新闻（医药）

2024-09-25

·Business Wire

New Study Demonstrates Power of Depixus’ Scalable Single Molecule Interactomics Platform to Accelerate RNA-Targeted Drug Development

PARIS--( BUSINESS WIRE )--A new research study published in Nature Communications highlights how Depixus’ scalable single molecule technology can provide detailed mechanistic insights into RNA-ligand binding, supporting the development of novel therapeutics. Based on magnetic force spectroscopy (MFS), Depixus’ large scale interactomics platform is the first analytical technology capable of exploring dynamic biomolecular interactions both in real time and from thousands of individual molecules in parallel. The study was led by Dr. John “Jay” Schneekloth, Jr. a leading expert in RNA-targeted drug discovery at the National Cancer Institute, part of the US National Institutes of Health. Depixus’ scalable MFS platform was used to probe the interactions between the Bacillus subtilis (Bsu) PreQ 1 bacterial riboswitch and either its natural ligand (PreQ 1 ) or a synthetic small molecule known as Compound 4. Riboswitches are structured sequences of RNA commonly found in the 5′ untranslated regions of bacterial mRNAs that help to control metabolic pathways. Ligands such as metabolites bind to the riboswitch, inducing a conformational change in the secondary structure and altering gene expression. This makes them an attractive group of novel antibacterial drug targets. In a key part of the study, Depixus’ MFS platform was used to precisely measure the effects of either PreQ 1 or Compound 4 binding on immobilized target riboswitch RNA aptamers. The results showed both ligands stabilized the RNA structure, and the effect of compound concentration was measured. Importantly, analysis of MFS data streams coming from individual interactions revealed that the two ligands had very distinct modes of action - a distinction that would have been missed using other analytical techniques that only generate surrogate or bulk, averaged measurements. Jimmy Ouellet, Chief Scientist at Depixus, said “This study highlights how our ability to carry out independent analysis of individual biomolecular interactions enables us to visualize RNA-ligand interactions in real time, gathering valuable insights into distinct mechanisms of action. With our large-scale MFS platform we now have a technology that can see biology as it really happens, exploring the mechanistic impact of compounds on their targets at the level of individual molecules, generating detailed information about binding kinetics and more.” Depixus’ unique platform delivers valuable data about a wide range of individual dynamic molecular interactions - including between RNA, DNA, proteins and small molecules - decoding disease mechanisms and unlocking faster routes to more effective therapies. Find out more at depixus.com Reference: Parmar S, et al. Nat Commun. (2024) 15:8173.

2023-01-31

·药时代

王明伟/柳红/杨德华领衔合作团队成功解析人源松弛素/胰岛素样肽受体4复合物三维结构

2023年1月31日（北京时间），由复旦大学基础医学院王明伟、中国科学院上海药物研究所柳红和杨德华领衔的合作团队在Nature Communications在线发表了题为“Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)”的研究论文。该论文首次报道了人源松弛素/胰岛素样肽受体4（Relaxin family peptide receptor 4, RXFP4）分别结合内源性配体胰岛素样肽5（Insulin-like peptide 5, INSL5）、小分子RXFP4/RXFP3双激动剂Compound 4及小分子RXFP4选择性激动剂DC591053并与Gi蛋白形成复合物的高分辨率冷冻电镜结构，不仅阐明了INSL5独特的受体识别模式，而且揭示了Compound 4拟肽作用的关键位点和DC591053受体亚型选择性的分子机制。RXFP4为A类G蛋白偶联受体（G protein-coupled receptor, GPCR），2003年首见于人类基因组数据库1，2005年被证实为INSL5的内源性受体2。INSL5属于松弛素/胰岛素超家族，1999年Conklin等人在研究该超家族保守的B链半胱氨酸基序（Motif）时，通过检索人类表达序列标签（Expressed sequence tags, EST）数据库而被发现3，二者均高表达于结直肠组织。2015年，王明伟课题组通过对RXFP4的多年研究发现其配体INSL5既可促进小鼠胰岛瘤细胞MIN-6分泌胰岛素，又可提高小鼠肠系L细胞GLUTag释放胰高血糖素样肽-1（Glucagon-like peptide-1, GLP-1）的能力；动物实验亦证实INSL5可改善小鼠的血糖稳态4。此外，INSL5/RXFP4还参与调控能量代谢、食欲调节和肠道蠕动等生理功能5。由于INSL5是由A链和B链通过3个二硫键连接的多肽，化学合成非常困难；现有小分子配体数量稀少，诺华公司报道的Compounds 1、2、3和4均为RXFP4/RXFP3双激动剂6，特异性低，从而限制了对RXFP4生物效应的深入研究和相关新药的发现。2020年，王明伟/杨德华团队通过高通量筛选获得了特异性靶向RXFP4的小分子化合物JK17，并在此基础上经过结构优化改造得到了靶点特异性更佳的激动剂9-(S)-14b8。遗憾的是，上述两个化合物都存在活性弱、毒性大和溶解不易等问题。参与本论文研究的国际合作团队在利用大肠杆菌表达、高密度发酵和专有蛋白纯化技术批量生产INSL5的同时，通过化合物筛选和基于四氢异喹啉母核的结构优化改造，发现了非肽类RXFP4选择性激动剂DC591053（pEC50 = 7.24 ± 0.12），且在NanoBiT系连技术9的助推下获得了分别与上述三种不同配体结合、颗粒均一和性状稳定的 RXFP4–Gi蛋白复合物。他们借助中国科学院上海药物研究所的300 kV冷冻电镜所拍摄的清晰图像和后继单颗粒三维重构，成功解析了分辨率各自为3.19 Å、3.03 Å和2.75 Å的INSL5–RXFP4–Gi、Compound 4–RXFP4–Gi及DC591053–RXFP4–Gi三个复合物的分子结构（图1）。图1. RXFP4–Gi分别结合INSL5、Compound 4和DC591053的冷冻电镜结构。a，INSL5–RXFP4–Gi复合物结构；b，Compound 4–RXFP4–Gi复合物结构及Compound 4的化学结构；c，DC591053–RXFP4–Gi复合物结构及DC591053的化学结构。研究显示，RXFP4识别INSL5的方式不同于已报道的A类GPCR：INSL5 B链羧基末端的α-螺旋深入受体跨膜域（Transmembrane domain, TMD），而A链则覆盖正构位点从而维持配体的完整性和结构稳定性。特别是B链羧基末端的R23B与RXPF4上的E1002.63（右上标数字为Ballesteros–Weinstein编号10，用于确定TMD氨基酸的相对位置）形成盐桥，而W24B除了与T1213.32、Q2055.39和R2085.42等残基形成众多极性作用网络外，亦可与W972.60及H2997.43发生与受体激活密切关联的堆叠效应（图2）。人为突变E1002.63、T1213.32和R2085.42导致INSL5完全失活，破坏W972.60、Q2055.39和H2997.43等残基也不同程度地影响了RXFP4的活化。图2. RXFP4识别INSL5的结构基础。a，INSL5与RXFP4结合的整体示意图；b，INSL5的B链羧基末端R23B和W24B深入RXFP4的正构位点并形成多个极性相互作用；c-e，RXFP4胞外环参与INSL5的识别。非选择性激动剂Compound 4也能深入RXFP4的结合口袋，其胍基模拟INSL5的B链R23B与RXFP4上的E1002.63形成盐桥，而吲哚母核则模拟W24B的吲哚环与周围残基形成广泛的相互作用；该小分子配体对RXFP4的激活能力在发生W972.60、E1002.63、T1213.32与H2997.43等残基的突变后显著降低（图3a-b）。然而，选择性激动剂DC591053则展现与Compound 4迥异的结合方式，其马琳环占据RXFP4独特的配体结合口袋（图3c-d），在3.29、3.33、5.39、5.42和7.39等位点上（Ballesteros–Weinstein编号10）与RXFP3的氨基酸差异明显，与亚型选择性相关（图3e）。这个发现得到了功能性实验数据的支持：置换RXFP3和RXFP4上述同源位点的氨基酸，Compound 4对RXFP4突变体L1183.29S+V1223.33S的作用没有显著变化，但DC591053的效价却降低20.9倍；较之Compound 4，DC591053激活Q2055.39H和R2085.42K等RXFP4突变体的能力也受到更大影响。可以预期，这项成果将有助于深入研究RXFP4的生理功能和开发高效的的选择性RXFP4小分子激动剂，同时也有望提升人们对胰岛素超家族成员多元识别相关受体的认识。图3. 小分子激动剂的拟肽作用及和DC591053选择性激活RXFP4的分子机制。a，Compound 4的结合口袋截面图；b，Compound 4与RXFP4的相互作用；c，DC591053特异性激活RXFP4；d，DC591053结合口袋截面图；e，小分子激动剂与受体相互作用模式示意。复旦大学基础医学院博士研究生陈彦、复旦大学基础医学院青年研究员周庆同和中国科学院上海药物所王江研究员为该论文的共同第一作者；复旦大学王明伟讲席教授、中国科学院上海药物研究所柳红研究员和杨德华研究员为该论文的共同通讯作者。合作者包括澳大利亚墨尔本大学Ross A.D. Bathgate教授、中国科学院上海药物所徐华强研究员和常州健亚生物科技有限公司沈纯博士等。该研究成果先后获得了国家自然科学基金委员会、国家科学技术部、国家卫生与健康委员会、中国科学院和上海市科学技术委员会等的经费资助。原文链接：https://doi.org/10.1038/s41467-023-36182-z（也可后台留邮箱，获取PDF版本）参考文献：Boels, K. & Schaller, H. C. Identification and characterisation of GPR100 as a novel human G-protein-coupled bradykinin receptor. Br J Pharmacol 140, 932-938 (2003)Liu, C. et al. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem 280, 292-300 (2005).Conklin, D. et al. Identification of INSL5, a new member of the insulin superfamily. Genomics 60, 50-56 (1999).Luo, X. et al. The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. Biochem J 466, 467-473 (2015).Hechter, D. et al. Reviewing the physiological roles of the novel hormone-receptor pair INSL5-RXFP4: a protective energy sensor? J Mol Endocrinol 69, R45-R62 (2022).DeChristopher, B. et al. Discovery of a small molecule RXFP3/4 agonist that increases food intake in rats upon acute central administration. Bioorg Med Chem Lett 29, 991-994 (2019).Lin, G. Y. et al. High-throughput screening campaign identifies a small molecule agonist of the relaxin family peptide receptor 4. Acta Pharmacol Sin 41, 1328-1336 (2020).Lin, L. et al. Design, synthesis and pharmacological evaluation of tricyclic derivatives as selective RXFP4 agonists. Bioorg Chem 110, 104782 (2021).Xu, Y. et al. A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2. Nat Commun 13, 2272 (2022).Juan A. B. et al. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods in Neurosciences 25, 366-428 (1995).封面图来源：nature推荐阅读礼来重磅新药被FDA拒批，理由如此「荒诞」，谁应该负这个责？「金翅雀」的消亡史，是多少Biotech的缩影！诺华First-in-class药物上市3年后，确证性试验结果出炉：未能击败安慰剂...推荐阅读王明伟/Vogt/杨德华/水雯箐领衔中美科学家深度解析重要靶点PI3Kα的结构与功能【首发】PNAS | 王明伟/杨德华团队揭示GLP-1受体小分子激动剂拟肽效应的的分子机制自然·通讯 | 人源血管活性肠肽受体2复合物三维结构成功解析重磅首发！中国科学家首次揭示「GIPR、GLP-1R和GCGR双重和三重激动剂药理作用的分子机制」！对新药创制意义重大！里程碑！PNAS | 人源全长PI3Kα复合物三维结构成功解析（附：邵峰院士、叶德全院长点评）PNAS | 生长激素释放激素受体的结构性信号偏向转导机制PNAS | 人源甲状旁腺激素受体2复合物三维结构成功解析eLife | 人源葡萄糖依赖性促胰岛素释放多肽受体三维结构成功解析我国科研人员发现判断前列腺癌预后的潜在生物标志物《自然•通讯》| 我国科学家发现B1类G蛋白偶联受体变构激动调节的分子机制Cell Research | 人源胰高血糖素样肽-2受体复合物三维结构成功解析Science | 解析新冠病毒奥密克戎文章！上海药物所徐华强团队发表中科院徐华强/尹万超团队联合攻关新冠病毒奥密克戎（Omicron）变异株刺突蛋白及其与受体和抗病毒抗体的复合物结构首发 | 中科院徐华强/尹万超团队联合攻关新冠病毒奥密克戎（Omicron）变异株刺突蛋白及其与受体和抗病毒抗体的复合物结构喜报 | 上海药物所徐华强课题组多巴胺受体研究成果荣登Cell封面讲座直播：2021年度诺贝尔生理学/医学奖花落谁家？| 药时代与返朴联合主办炎炎红镜东方开，明朝日月换新天！——邵峰院士与邓天敬博士联手打造炎明生物邵峰院士力挺的细胞焦亡，彻底火了点击报名参会！

100 项与 compound 4(英矽智能) 相关的药物交易

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