更新于：2024-11-01

SULT1A1

更新于：2024-11-01

基本信息

别名

Aryl sulfotransferase 1、HAST1/HAST2、P-PST

+ [12]

简介

Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine groupe. Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. Displays broad substrate specificity for small phenolic compounds. Plays an important role in the sulfonation of endogenous molecules such as steroid hormones and 3,3'-diiodothyronin (PubMed:16221673, PubMed:12471039, PubMed:22069470, PubMed:21723874, PubMed:10199779, PubMed:7834621). Mediates the sulfate conjugation of a variety of xenobiotics, including the drugs acetaminophen and minoxidil (By similarity). Mediates also the metabolic activation of carcinogenic N-hydroxyarylamines leading to highly reactive intermediates capable of forming DNA adducts, potentially resulting in mutagenesis (PubMed:7834621). May play a role in gut microbiota-host metabolic interaction. O-sulfonates 4-ethylphenol (4-EP), a dietary tyrosine-derived metabolite produced by gut bacteria. The product 4-EPS crosses the blood-brain barrier and may negatively regulate oligodendrocyte maturation and myelination, affecting the functional connectivity of different brain regions associated with the limbic system.

关联

项与 SULT1A1 相关的药物

YC-1

靶点

SULT1A1

作用机制

SULT1A1 modulators

在研机构

National Institutes of Health [+1]

原研机构

The Massachusetts General Hospital [+1]

在研适应症

肝癌

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

FIS103

靶点

SULT1A1

作用机制

SULT1A1 modulators

在研机构

Fannin Partners LLC

原研机构

Fannin Partners LLC

在研适应症

肾细胞癌

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

100 项与 SULT1A1 相关的临床结果

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100 项与 SULT1A1 相关的转化医学

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0 项与 SULT1A1 相关的专利（医药）

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983

项与 SULT1A1 相关的文献（医药）

2025-01-01·Journal of Affective Disorders

Causal effects of gut microbiota, metabolites, immune cells, liposomes, and inflammatory proteins on anorexia nervosa: A mediation joint multi-omics Mendelian randomization analysis

Article

作者: Bi, Tianyu ; Li, Zeyang

BACKGROUNDAnorexia nervosa (AN) is a significant psychological disorder influenced by environmental and genetic elements. Emerging research highlights the pivotal role of the gut microbiome in the development of diverse mental health conditions. This study aims to explore the causal effects and interactions of the gut microbiome, metabolites, immune cells, lipids, and inflammatory proteins on the risk of anorexia nervosa through mediation and multi-omics Mendelian Randomization (MR) analysis.METHODSThis study used data from the FinnGen genome-wide association study (GWAS) of AN (N = 402,625), integrated with GWAS data on 473 of gut microbiota (N = 5959), 233 metabolites (N = 136,016), 731 immune cells (N = 3757), 179 lipids (N = 7174), and 91 inflammatory proteins (N = 14,824). This study used the univariate MR (UVMR), mediation MR analysis, and sensitivity analysis to assess the potential causal associations between these biomarkers and AN.RESULTSThe inverse variance weighted (IVW) results suggest that 25 gut microbiota have causal effects on AN. Firmicutes E (OR: 0.294, 95 % CI: 0.107-0.806, P = 0.017), RUG147 (OR: 0.386, 95 % CI: 0.151-0.990, P = 0.048), CAG-977 (OR: 0.562, 95 % CI: 0.378-0.837, P = 0.005), Desulfobacterota A (OR: 0.651, 95 % CI: 0.466-0.909, P = 0.012), CAG-269 sp002372935 (OR: 0.673, 95 % CI: 0.483-0.937, P = 0.019), Klebsiella (OR: 0.684, 95 % CI: 0.566-0.827, P = 0.00009), Desulfovibrionia (OR: 0.706, 95 % CI: 0.538-0.926, P = 0.012), Klebsiella pneumoniae (OR: 0.737, 95 % CI: 0.600-0.906, P = 0.004), Desulfovibrionales (OR: 0.786, 95 % CI: 0.631-0.979, P = 0.031), CAG-776 (OR: 0.787, 95 % CI: 0.632-0.980, P = 0.032), Desulfovibrionaceae (OR: 0.788, 95 % CI: 0.635-0.978, P = 0.030). 13 gut microbiota were risk factors for AN, including Parachlamydiales (OR: 3.134，95%CI: 1.185-8.287, P = 0.021), Paenibacillus J (OR: 2.366，95%CI: 1.305-4.29, P = 0.005), Gillisia (OR: 1.947，95%CI: 1.135-3.339, P = 0.016), UBA1191 (OR: 1.856，95%CI: 1.221-2.822, P = 0.004), UBA7703 (OR: 1.843，95%CI: 1.032-3.289, P = 0.039), Faecalicatena sp002161355 (OR: 1.788，95%CI: 1.114-2.870, P = 0.016), Johnsonella ignava (OR: 1.742，95%CI: 1.031-2.944, P = 0.038), Staphylococcus aureus (OR: 1.614, 95%CI: 1.007-2.588, P = 0.047), Comamonas (OR: 1.522，95%CI: 1.004-2.307, P = 0.048), Ruminococcus D (OR: 1.24，95%CI: 1.050-1.464, P = 0.011), CAG-349 (OR: 1.198，95%CI: 1.048-1.370, P = 0.008), Ruminococcus D bicirculans (OR: 1.175，95%CI: 1.001-1.379, P = 0.048), CAG-177 (OR: 1.272，95%CI: 1.077-1.503, P = 0.005). Reverse MR analysis showed that causal effect of AN on 18 gut microbiota, but to a lesser extent. 12 metabolites have causal effects on AN. There are 7 protective factors, including glucose levels (OR: 0.700, 95%CI: 0.550-0.893, P = 0.004), isoleucine levels (OR: 0.769, 95%CI: 0.602-0.983, P = 0.036), phospholipids in large VLDL (OR: 0.856, 95%CI: 0.736-0.996, P = 0.044), total lipids in large VLDL (OR: 0.860, 95%CI: 0.740-0.999, P = 0.049), total lipids in small VLDL (OR: 0.863, 95%CI: 0.751-0.992, P = 0.038), free cholesterol in small VLDL (OR: 0.86, 95%CI: 0.752-0.996, P = 0.044), and free cholesterol in medium VLDL (OR: 0.866, 95%CI: 0.752-0.998, P = 0.047). There are 5 risk factors, including estimated degree of unsaturation (OR: 1.174, 95%CI: 1.009-1.367, P = 0.039), free cholesterol to total lipids ratio in small VLDL (OR: 1.199, 95%CI: 1.017-1.414, P = 0.031), phospholipids to total lipids ratio in small VLDL (OR: 1.216, 95%CI: 1.008-1.467, P = 0.041), total cholesterol levels in small HDL (OR: 1.241, 95%CI: 1.008-1.530, P = 0.042), and phospholipids to total lipids ratio in medium VLDL (OR: 1.280, 95%CI: 1.055-1.553, P = 0.012). Reverse MR analysis showed that AN had a causal effect on 15 metabolites. Mediation analysis reveals that the estimated degree of unsaturation mediates 0.69 % of the effect of Klebsiella pneumoniae on AN. Total lipids in small VLDL mediate 0.358 % of the effect of CAG-177 on AN, with a mediated proportion of 1.490 %. The mediation proportions for Estimated degree of unsaturation and Total lipids in small VLDL are relatively small. 36 immune cells have causal effects on AN. There are 7 protective factors, including Switched memory B cells %B cell (OR: 0.892，95%CI: 0.801-0.994, P = 0.038), CD127-CD8+ T cell absolute count (OR: 0.888，95%CI: 0.789-1.000, P = 0.049), IgD + CD24- B cell (OR: 0.917，95%CI: 0.862-0.975, P = 0.006), HVEM+ T cell (OR: 0.945，95%CI: 0.894-0.999, P = 0.045), CD40 + CD14 + CD16- monocyte (OR: 0.937，95%CI: 0.882-0.996, P = 0.038), CD64 + CD14 + CD16- monocyte (OR: 0.966，95%CI: 0.939-0.993, P = 0.016), CD8+ natural killer T cells (OR: 0.911，95%CI: 0.836-0.992, P = 0.032), HLA-DR+ T cells (OR: 0.921，95%CI: 0.866-0.980, P = 0.010), CD28-CD8+ T cells (OR: 0.886，95%CI: 0.792-0.991, P = 0.034). There are 26 risk factors. Reverse MR analysis showed that AN had a causal effect on 31 immune cells. AN increases the expression levels of five types of immune cells, including CD40 + CD14-CD16+ monocytes (OR: 1.087，95%CI: 1.004-1.177, P = 0.041), PDL-1+ CD14-CD16+ monocytes (OR: 1.082，95%CI: 1.002-1.168, P = 0.046), CD45+ CD33dim HLA-DR+ cells (OR: 1.145，95%CI: 1.019-1.287, P = 0.023), CD45+ basophils (OR: 1.164，95%CI: 1.036-1.307, P = 0.011), CD8+ natural killer T cells (OR: 1.102, 95%CI: 1.015-1.196, P = 0.020), and also decreases the expression levels of 26 immune cells. 6 liposomes showed exhibit protective effects against AN, including phosphatidylcholine (18:0_20:3) levels (OR: 0.852, 95%CI: 0.740-0.981, P = 0.026), phosphatidylcholine (O-18:2_18:1) levels (OR: 0.800, 95%CI: 0.672-0.952, P = 0.012), phosphatidylinositol (18:0_18:1) levels (OR: 0.873, 95%CI: 0.773-0.986, P = 0.029), phosphatidylinositol (18:1_18:2) levels (OR: 0.844, 95%CI: 0.734-0.971, P = 0.018), sphingomyelin (d38:1) levels (OR: 0.903，95%CI: 0.820-0.995, P = 0.039), and triacylglycerol (56:4) levels (OR: 0.786, 95%CI: 0.660-0.936, P = 0.007). There are 3 risk factors, including diacylglycerol (16:1_18:1) levels (OR: 1.208, 95%CI: 1.040-1.404, P = 0.014), phosphatidylcholine (18:1_18:3) levels (OR: 1.237, 95%CI: 1.003-1.526, P = 0.047), and phosphatidylinositol (16:0_20:4) levels (OR: 1.148, 95%CI: 1.003-1.314, P = 0.045). Reverse MR analysis showed that AN had a causal effect on 3 phosphatidylcholine (15:0_18:2) levels (OR: 1.075, 95%CI: 1.001-1.154, P = 0.048), phosphatidylcholine (O-16:2_18:0) levels (OR: 1.078, 95%CI: 1.002-1.159, P = 0.043), and triacylglycerol (51:1) levels (OR: 0.919, 95%CI: 0.850-0.994, P = 0.035). 6 inflammatory proteins have causal effects on AN, with protective factors including Glial cell line-derived neurotrophic factor levels (OR: 0.822，95%CI: 0.692-0.978, P = 0.027) and Interleukin-15 receptor subunit alpha levels (OR: 0.886, 95%CI: 0.789-0.995, P = 0.041) and risk factors including CC motif chemokine 4 levels (OR: 1.126, 95%CI: 1.011-1.254, P = 0.031), Interleukin-12 subunit beta levels (OR: 1.135, 95%CI: 1.033-1.248, P = 0.008), Monocyte chemoattractant protein-1 levels (OR: 1.152, 95%CI: 1.010-1.314, P = 0.035), and Sulfotransferase 1A1 levels (OR: 1.166, 95%CI: 1.006-1.351, P = 0.042). Reverse MR analysis showed that AN had a causal effect on Transforming growth factor-alpha (OR: 1.054，95%CI: 1.010-1.101, P = 0.016).CONCLUSIONSThis study used large-scale and novel GWAS data, for the first time reveals through mediation analysis and multi-omics MR analysis the roles of gut microbiota, metabolites, immune cells, lipids, and inflammatory proteins in the pathogenesis of AN. These findings provide new biomarkers and targets for further prevention and treatment strategies.

2024-12-01·Cytokine

Causal relationship between circulating inflammatory proteins and risk of different types of encephalitis: A two-sample Mendelian randomization study

Article

作者: Yang, Shiqiang ; Wang, Shiqiang ; Yang, Anqiang ; Peng, Hua ; Hui, Xuhui ; Liu, Yanwei

BACKGROUNDCytokines are potent molecules of the immune response. They act at the site of inflammation and circulate in the bloodstream. However, there are few studies on encephalitis and circulating inflammatory proteins.METHODSIn this study, Mendelian randomization (MR) was used to explore the potential causal effect of 91 circulating inflammatory proteins on 3 different types of encephalitis. Causal effects were examined using Steiger, MR-Egger, weighted median, and inverse variance weighting (IVW) methods. IVW methods were primarily used for results interpretation. In addition, sensitivity analyses were performed, including assessment of heterogeneity, horizontal pleiotropy, and Leave-one-out techniques.RESULTSWe subjected 91 circulating inflammatory proteins to MR analysis of causality with each of the three types of encephalitis. The results suggested that the inflammatory factors with a potential causal relationship with viral encephalitis were caspase 8, C-X-C motif chemokine 6, interleukin-10, interleukin-15 receptor subunit alpha, interleukin-7, and TNF-beta. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are beta-nerve growth factor, cystatin D, interleukin-7, Latency-associated peptide transforming growth factor beta 1,and neurotrophin-3.Inflammatory factors potentially causally associated with autoimmune encephalitis are C-C motif chemokine 25, hepatocyte growth factor, latency-associated peptide transforming growth factor beta 1, programmed cell death 1 ligand 1, sulfotransferase 1A1, and tumor necrosis factor.CONCLUSIONThis finding identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. It also suggests the therapeutic potential of modulating the levels of these cytokines. A basis for further research is provided.

2024-12-01·Clinical Proteomics

Identification of novel proteins in inflammatory bowel disease based on the gut-brain axis: a multi-omics integrated analysis

Article

作者: Xu, Yifeng ; Yan, Zhaoqi ; Liu, Liangji

BACKGROUNDThe gut-brain axis has garnered increasing attention, with observational studies suggesting its involvement in the disease activity and progression of inflammatory bowel disease (IBD), but the precise mechanisms remain unclear.MATERIALS AND METHODSIn this study, we aimed to investigate "novel proteins" underlying IBD in the brain using a comprehensive multi-omics analysis approach. We performed integrated analyses of proteomics and transcriptomics in the human prefrontal cortex (PFC) tissue, coupled with genome-wide association studies (GWAS) of IBD, crohn's disease (CD), and ulcerative colitis (UC). This included performing protein-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with IBD and its subtypes.RESULTSPWAS analyses identified and confirmation 9, 9, and 6 brain proteins strongly associated with IBD, CD, and UC, respectively. Subsequent MR analyses revealed that increased abundance of GPSM1, AUH, TYK2, SULT1A1, and FDPS, along with corresponding gene expression, led to decreased risk of IBD. For CD, increased abundance of FDPS, SULT1A1, and PDLIM4, along with corresponding gene expression, also decreased CD risk. Regarding UC, only increased abundance of AUH, along with corresponding gene expression, was significantly associated with decreased UC risk. Further TWAS and colocalization analyses at the transcriptome level supported strong associations of SULT1A1 and FDPS proteins with reduced risk of IBD and CD.CONCLUSIONThe two "novel proteins," SULT1A1 and FDPS, are strongly associated with IBD and CD, elucidating their causal relationship in reducing the risk of IBD and CD. This provides new clues for identifying the pathogenesis and potential therapeutic targets for IBD and CD.

项与 SULT1A1 相关的新闻（医药）

2024-08-11

·生物探索

Cell Metabolism | 营养素影响胰岛素分泌的蛋白质组学密码

引言众所周知，葡萄糖驱动胰岛素分泌，以维持能量稳态。目前对人胰岛素的研究通常只使用葡萄糖刺激，然而，另外两大宏量营养素--蛋白质和脂肪有没有可能也调节胰岛素的释放？迄今为止，非碳水化合物营养素对胰岛素分泌的影响还没有充分研究，针对人体的碳水化合物、蛋白质和脂肪的胰岛素分泌反应水平变化和机制仍未被揭示。对营养素刺激人类胰岛素分泌的研究有助于扩大我们的临床认识，然而我们对于这个问题的有限了解大多来自于对啮齿动物的研究。全面了解营养素诱导的人类胰岛素分泌在2型糖尿病（T2D）和相关新兴研究中具有重要意义。近日，来自加拿大英属哥伦比亚大学和温哥华海岸健康研究所的James D.Johnson、Jelena Kolic研究小组与加拿大阿尔伯塔大学等单位合作在Cell Metabolism杂志上发表题为Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease的论文，这篇文章对来自非糖尿病（ND）和2型糖尿病（T2D）人类胰岛在三大主要宏量营养素包括碳水化合物、蛋白质和脂质影响下的胰岛素分泌动力学进行了综合分析，同时辅以转录组学和蛋白质组学分析，发现了胰岛的分子特征，并鉴定了不同的蛋白质簇，这些蛋白质簇可以预测胰岛素对碳水化合物、蛋白质和脂质的分泌反应，首次并排比较了人类胰岛和干细胞来源的胰岛之间营养反应和蛋白质组。这是目前最大的人类胰岛数据集，揭示了营养反应的多样性及机制。这一资源有望为糖尿病患者提供更多的个性化治疗建议。 2016年至2022年间，作者系统地测量了来自140名供体的胰岛对碳水化合物（15或6 mM葡萄糖）、氨基酸（5 mM亮氨酸）和脂质（1.5 mM油酸/棕榈酸混合物）的胰岛素分泌反应。证实碳水化合物是最强的胰岛素促分泌剂，其次是氨基酸，然后是脂肪。T2D患者的胰岛在葡萄糖和脂肪酸刺激下胰岛素分泌减少，但氨基酸刺激下的胰岛素分泌未受影响。图1: ND和T2D胰岛之间的差异丰度蛋白质(Credit: Cell Metabolism) 为了更好地了解ND和T2D患者的胰岛中分泌反应与基因表达变化之间的关系，作者对这些胰岛进行了全面的转录组和蛋白质组分析。通过RNA测序和质谱法分析了20,000多个mRNA和近8,000个蛋白质，数据确定了与葡萄糖刺激的胰岛素分泌相关的关键蛋白在T2D中减少，包括例如ARG2、NAT8L、HADH、PPM1K、AMACR、PFKFB2、G6PC2、ERO1B、OTULINL、ATP2A3和CASR等（图1）。不同个体的胰岛对营养素刺激的胰岛素分泌反应存在显著个体差异，特别是一些胰岛对脂肪酸的反应比葡萄糖更强烈，这一发现挑战了长期以来认为饮食脂肪对胰岛素释放的影响可以忽略不计的传统观点。作者利用共表达网络分析揭示了与胰岛功能紧密相关的蛋白质网络（图2），确定了18个关键蛋白质模块，其中9个模块与胰岛功能直接相关。与营养素刺激的胰岛素分泌呈正相关的模块参与细胞骨架、线粒体代谢、胰岛素加工等关键过程。在蛋白质运输和定位中起作用的模块与KCl刺激的胰岛素分泌呈正相关，但与脂质刺激的胰岛素分泌呈负相关，表明人类胰岛中的这些蛋白质网络模块支持对刺激的差异化响应。图2: 共表达网络分析确定的18个不同的蛋白质模块（方块内显示Pearson相关系数和p值，红色阴影表示正相关，蓝色阴影表示负相关，黑框表示显著相关）(Credit: Cell Metabolism) 接下来，作者研究分析了mRNA和蛋白质丰度与胰岛特征的关联，特别是与功能的关系。发现胰岛供体的年龄与涉及溶酶体降解、细胞衰老、炎症、线粒体功能障碍等蛋白质的丰度呈正相关，例如PPT、SCARB2、ASAH1、P2X436和NADPH、FDXR等。此外，蛋白质丰度与糖化血红蛋白水平相关，有趣的是这类蛋白还涉及癌症的进展，例如YIF1A、UBAP1、STX5等，这可能和血糖控制不佳与多种癌症风险增加有关。胰岛功能分析揭示了脂质是胰岛素释放的重要调节因子，并鉴定了与总体胰岛分泌能力相关的关键蛋白质。作者建立了一个在线资源，可以显示检测到的蛋白质、供体特征、胰岛分离参数和胰岛功能之间的关系（www.humanislets.com）。在基础葡萄糖条件下，约8%的供体胰岛对脂质的胰岛素分泌反应异常强烈，对脂质高反应的胰岛WNT4降低，表明胰岛可能处于较不成熟状态；同时，HNF1B、SULT1A1和PDGFRA表达升高。约9%的供体胰岛对亮氨酸的胰岛素分泌反应强于高葡萄糖。治疗糖尿病非常有潜力的一种疗法是利用胚胎干细胞分化为β细胞替代物，胚胎干细胞衍生的胰岛样团簇与人类胰岛相比，其基础胰岛素释放水平仅为1/10，其基础胰岛素释放及葡萄糖、氨基酸反应性低于人类胰岛，它可能更偏好非葡萄糖底物。蛋白质组学分析揭示了干细胞胰岛样团簇与人类胰岛的显著差异，包括未成熟β细胞标记物的增加及脂肪酸转运和代谢相关蛋白的上调，人胚胎干细胞衍生的胰岛样团簇具有脂质响应性。高胰岛素血症与多种健康问题相关，这项研究在人胰岛中确定了碳水化合物、蛋白质和脂质三种营养素的胰岛素分泌反应，搭建了在线数据平台：www.humanlislands.com作为胰岛深层表型网络资源。作者的证据还表明营养特异性胰岛素分泌在普通人群中存在异质性，9%的供体胰岛对氨基酸有反应，8%的供体胰岛对脂肪酸的反应大于其葡萄糖刺激的胰岛素反应，这意味着这些胰岛与高葡萄糖引起的胰岛素分泌反应的胰岛截然不同，作者通过干细胞中的观察，推测这种脂质反应性与β细胞不成熟有关。这项研究为针对胰岛对碳水化合物、蛋白质和脂质响应的多样性提供个性化营养治疗奠定了基础。图3：三大主要宏量营养素包括碳水化合物、蛋白质和脂质对人胰岛分泌反应的影响研究(Credit: Cell Metabolism) 参考文献 https://doi.org/10.1016/j.cmet.2024.06.001 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

信使RNA细胞疗法

2024-01-16

·GlobeNewswire-Health Care

Stalicla Secures $17.4 Million in Series B Financing to Propel Precision Neuro Advancements

Geneva, Switzerland, January 16th, 2024 – Stalicla SA, a clinical-stage biopharmaceutical company advancing precision medicine pipelines for neuropsychiatric and neurological disorders, announces the successful completion of the first closing of its Series B financing round, securing $17.4 million. Led by SPRIM Global Investments Pte, Ltd, with key participation from core investors, this funding includes a $3.8 million credit facility. The proceeds will be utilized for: (i) preparation of Stalicla’s pioneering precision Autism Spectrum Disorder (ASD) Phase 2 trial – STP1; (ii) the establishment of its STP7 mGluR5 Negative Allosteric Modulator (mGluR5 NAM) platform, including the launch a Phase III study in Substance Use Disorders (SUDs) slated for 2025, fully supported by the NIH /National Institute on Drug Abuse; (iii) the ramp up of its ongoing biosampling/ patient identification trial STA-B-001 currently enrolling in sites in the USA, Spain and Australia. Alongside these key developments, Stalicla will further strengthen the package supporting its second precision ASD asset, STP2. Lynn Durham, CEO of Stalicla commented: “This financial backing underscores Stalicla's role as a trailblazer in the neuro precision space with first applications in precision psychiatry. Additionally, our STP7 mGluR5 NAM platform is offering multifaceted advanced clinical development opportunities in the wider neurology space in a timely period of recent clinical progress & increased transaction activity level in the neurology and neuropsychiatry space. There has never been a more promising time to advance transformative treatment options for millions of patients with brain diseases and Stalicla is determined to play a key role in this progress.” To support these advancements, Stalicla will strengthen its Management Team and Board of Directors, reinforcing the foundation for the exciting journey ahead. About STALICLA SASTALICLA is a precision molecular neuroscience clinical stage company, advancing through its DEPI precision neuro platform 2 precision autism assets: STP1 and STP2. Following the in-licensing of mavoglurant from Novartis in 2023, STALICLA has also established an advanced mGLuR5 NAM platform with multi-faceted late-stage clinical development opportunities.For further information, please visit: https://stalicla.com/ Contact:Stalicla SALynn Durham, Founder & CEOLynn.durham@stalicla.com Attachment Press Release 2024-01-SeriesB_final

临床2期临床3期

2023-07-14

·药智网

2023年抗肿瘤药物新靶点（9个）

在抗肿瘤药物研发中，新靶点的不断涌现，对肿瘤治疗具有重要意义，逐渐实现了精准医疗方法，克服了耐药性，并扩大了治疗领域。本文将盘点一下，过去一年里，新发现的或者具有新适应症的抗肿瘤药物靶点。01胃癌新靶点：claudin-18.2claudin-18.2(CLDN 18.2)是一种在胃粘膜中广泛存在的紧密连接蛋白。在正常情况下，它负责将相邻的胃粘膜上皮细胞牢固地连接在一起，防止胃内的食物和消化液从细胞间隙渗漏到人体内部环境中。然而，在肿瘤发展过程中，CLDN 18.2广泛表达于多种消化道肿瘤中，并参与肿瘤的增殖、分化和迁移等过程。国内外目前已有多款的靶向CLDN 18.2药物在研。Zolbetuximab是首个靶向CLDN 18.2的药物。加入Zolbetuximab与mFLOFOX6联合用药与单独mFLOFOX6化疗相比，晚期胃癌患者的中位无进展生存期延长近2个月，达到10.61个月，中位总生存期从15.54个月延长到18.23个月，患者的死亡风险和进展风险均下降了25%。国内在研的药物包括创胜集团自主研发的TST001和科济药业开发的CAR-T疗法，名为CT041，均取得了积极进展。02肺鳞癌靶点：mTOR非小细胞肺癌一直是靶向治疗的重要领域，目前众多靶向药只能使肺腺癌患者获益，而另一个主要肺癌亚型——肺鳞癌，只有很少一部分患者可以接受靶向治疗。Sapanisertib通过靶向KEAP1/NRF2通路下游的mTOR分子，并在晚期难治性肺鳞癌患者中取得了27%的客观缓解率和中位无进展生存期达到8.9个月。目前，正在进行Sapanisertib联合PD-1治疗晚期NRF2突变肺鳞癌的研究。03前列腺癌新靶点：PI5P4Kα、TRABID、PODXL（1）PI5P4Kα：磷脂酰肌醇激酶家族在肿瘤的发生、发展中发挥着重要作用，是抗肿瘤药物研究的重要靶点。2023年2月1日，一篇发表在Science Advances的文章中，研究人员对磷脂酰肌醇-5-磷酸-4-激酶（PI5P4K）的功能进行了研究，验证了PI5P4Kα亚型对雄激素受体（AR）信号传导的影响，该信号通路对前列腺癌细胞存活起到支持作用。研究表明，雄激素剥夺会影响磷脂酰肌醇的含量，并增加细胞内磷脂酰肌醇（4,5）二磷酸水平，表明磷脂酰肌醇的调节在雄激素剥夺期间前列腺癌代谢应激适应中变得越来越重要。该研究支持将PI5P4Kα作为潜在靶点，以解决前列腺癌治疗中不断增加的抵抗性难题。（2）TRABID：2023年3月31日，发表于Nature Communications一项研究证明了TRABID去泛素化酶可与53BP1结合，并在双链断裂位点上调节53BP1的稳定。前列腺癌细胞中过表达TRABID的情况下，癌细胞对PARP抑制剂表现出高度敏感性。该研究指出，TRABID通过在双链断裂位点上延长53BP1的存在，促进了非同源末端连接修复而非同源重组，这表明TRABID过表达可以用作预测前列腺癌中同源重组缺陷和PARP抑制剂治疗潜力的指标。（3）PODXL：糖萼成分和唾液粘蛋白足萼蛋白（PODXL）是一种跨膜蛋白，其升高的表达与肿瘤的不良临床结果相关。一篇发表于2023年2月3日的Science Advances文章中，报道了PODXL可以作为半乳糖凝集素-3（GAL3）的诱饵受体，从而导致PODXL-GAL3相互作用的释放。通过实验，研究人员确定了控制PODXL转变为促转移糖萼成分的分子机制，并揭示了PODXL作为诱饵受体可以减轻GAL3的侵袭抑制作用。研究证明这种水平的变化可以用于识别具有高度转移和预后不良的前列腺癌患者。04肝癌新靶点：SULT1A1、PRRS35（1）SULT1A1：今年3月13日发表于Nature Cancer的一篇文章介绍了成人肝脏恶性肿瘤（包括肝内胆管癌和肝细胞癌）的研究成果。这种肿瘤是全球癌症相关死亡的第二大原因。该研究中，通过高通量筛选、蛋白质组学和体外耐药模型，研究人员确定了一种名为YC-1的小分子化合物，对来自两种肝癌类型的细胞系亚群具有选择性活性。研究数据证明，这种选择性活性与肝脏固有的胞质磺基转移酶SULT1A1的表达有关。通过计算分析，研究人员还发现了一类更广泛依赖于SULT1A1的抗癌化合物。这项研究表明，SULT1A1有可能成为肝癌药物开发的潜在新靶点。（2）PRRS35：肝细胞癌进展过程中，肝细胞分泌蛋白组会发生动态变化，这不仅是肿瘤发生的结果，也是导致肿瘤发展的致病因素之一。最近发表于Nature Communications的一篇文章揭示了肝细胞癌中蛋白酶PRSS35的肿瘤抑制作用。研究表明，活性的PRSS35可以抑制CXCL2的蛋白质水平，进而抑制肝细胞癌的进展。该研究扩展了我们对肝细胞分泌蛋白在癌症发展中作用的认识，并为将PRSS35作为治疗靶点或诊断生物标志物进行临床转化提供了基础。05胰腺癌靶点：RBFOX2胰腺导管腺癌（PDAC）是一种具有高度侵袭性和强大转移能力的恶性肿瘤。目前，尚不清楚导致PDAC转移的驱动基因突变是什么。最近发表在Nature期刊上的一篇研究表明，在源自患者异种移植（PDX）的转移性PDAC细胞系中，过表达RBFOX2基因会显著降低这些细胞的体外和体内转移能力。相反，在原发性胰腺肿瘤细胞系中，RBFOX2基因的耗竭则增加了这些细胞的转移潜力。这些发现表明RBFOX2可能在抑制PDAC转移方面具有潜在作用。该研究为深入了解PDAC的转移机制提供了重要线索，并为利用RBFOX2基因的剪接调控作为PDAC的潜在治疗策略奠定了基础。06胶质母细胞瘤靶点：FGL2纤维蛋白原样2（FGL2）在病毒感染和癌症发展中具有凝血酶原酶活性和免疫调节功能。研究表明，表达FGL2特异性单链可变片段（T-αFGL2）的T细胞可以诱导肿瘤特异性CD8+组织驻留记忆T（TRM）细胞，从而防止胶质母细胞瘤复发。这些CD8+TRM细胞展现出扩展的T细胞受体库，并能够排斥神经胶质瘤细胞。通过增加特定信号分子的数量，T-αFGL2细胞治疗有望增加CD69+CD8+脑驻留记忆T细胞的数量，对预防胶质母细胞瘤复发具有重要意义。因此，FGL2被认为是胶质母细胞瘤免疫治疗中一个有吸引力的靶点。小结以上是今年在多种癌症中具有重要意义的新靶点，除此之外，在其他肿瘤治疗方面，也有新靶点的应用，比如在2023年的ASCO大会上，来自梅奥医学中心Christina Wu教授，对结直肠癌（CRC）中四个新型治疗靶点，包括HER2扩增、KRAS G12C突变、NTRK融合和RET融合进行了重要的临床研究总结和报告；ADC药物方面，也有众多靶点被运用，比如FolRa、TROP2、ITGB6等。药物的新靶点的鉴别，对推进癌症治疗具有重要意义，为克服抗药性的、实现了精准医疗提供了新的选择。这一领域的持续研究和创新将有助于为癌症患者提供更有效、更有针对性和个性化的治疗，最终改善患者的治疗效果和生活质量。声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八角转载开白 | 马老师 18996384680（同微信）商务合作 | 张武龙 13368443108（同微信）阅读原文，是昨天最受欢迎的文章哦

免疫疗法细胞疗法临床研究