This randomized phase II trial studies how well trametinib with or without Akt inhibitor GSK2141795 (GSK2141795) works in treating patients with uveal melanoma that has spread to other parts of the body (metastatic). Trametinib and GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective with or without GSK2141795 in treating patients with metastatic uveal melanoma.

开始日期2013-11-21

申办/合作机构

National Cancer Institute

NCT01989598

/ Completed临床2期IIT

A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory Multiple Myeloma

This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

开始日期2013-10-30

申办/合作机构

National Cancer Institute

NCT01902173

/ Completed临床1/2期IIT

Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination With Dabrafenib and Trametinib in Patients With BRAF Mutant Cancer

This phase I/II trial studies the side effects and the best dose of uprosertib when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IIIC-IV cancer. Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with dabrafenib and trametinib may be a better treatment for cancer.

开始日期2013-10-08

申办/合作机构

National Cancer Institute

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100 项与 Uprosertib 相关的临床结果

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100 项与 Uprosertib 相关的转化医学

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100 项与 Uprosertib 相关的专利（医药）

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项与 Uprosertib 相关的文献（医药）

2025-04-01·MOLECULAR DIVERSITY

An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs

Article

作者: Etikyala, Umadevi ; Manga, Vijjulatha ; Dalimba, Udayakumar ; Reddyrajula, Rajkumar ; Vani, T ; Kuchana, Vinutha

Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R² and Q² values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

2025-02-01·ADVANCED FUNCTIONAL MATERIALS

Advanced Hierarchical Computational Modeling‐Based Rational Development of Platinum (II) Nanocomplex to Improve Lung Cancer Therapy

Article

作者: Yang, Da ; Li, Song ; Huang, Haozhe ; Chen, Shangyu ; Ji, Beihong ; Li, Shichen ; Burns, Timothy F ; Huang, Yixian ; Luo, Zhangyi ; Sun, Jingjing ; Wang, Junmei ; Li, Sihan ; Chen, Yuang ; Bain, Daniel J

Abstract:

Cancer stem cells (CSCs) are known to be one of the determining factors that contribute to therapeutic resistance. However, much remains to be understood about the reprogramming network leading to the generation of CSCs driven by chemotherapy. In this study, guided by bioinformatics study, deeper insight is uncovered and provided into the CSC enrichment mechanism driven by cisplatin (CDDP) treatment. It is discovered that CDDP can repopulate the level of CSC by activating AKT1 oncogenic pathway that is further enhanced by COX‐2 inflammatory signaling. Simultaneously blocking these two pathways can synergistically restrain the number of CSCs. Under the guidance of advanced hierarchical computational modeling, including molecular docking, molecular dynamics (MD) simulation and binding free energy analysis, MK‐2206 is selected as the AKT1 inhibitor to achieve optimal codelivery of CDDP, MK‐2206 and 5‐ASA (COX‐2 inhibitor) through 5‐ASA‐derivatized dual functional immunostimulatory nanocarrier (PASA). This triple combination (PASA/CDDP/MK‐2206) significantly reduces tumor burden in both orthotopic and metastatic lung cancer models. Mechanistic studies show that this improved therapeutic activity is due to elimination of CSCs and reversal of the immunosuppressive tumor microenvironment. This study suggests that PASA/CDDP/MK‐2206 may represent a simple and effective lung cancer therapy via reversing CSCs‐associated chemoresistance.

2025-01-01·NATURE GENETICS

A multilineage screen identifies actionable synthetic lethal interactions in human cancers

Article

作者: Fong, Samson H ; Mali, Prashant ; White, Michael A. ; Kuenzi, Brent M ; Mattson, Nicole M. ; Kuenzi, Brent M. ; Kreisberg, Jason F ; Hager, Jeffrey H ; Munson, Brenton P. ; Munson, Brenton P ; Shen, John Paul ; Licon, Katherine ; Hager, Jeffrey H. ; Ideker, Trey ; Bergendahl, Sarah ; White, Michael A ; Fong, Samson H. ; Bojorquez-Gomez, Ana ; Lee, John ; Ford, Kyle ; Mattson, Nicole M ; Kreisberg, Jason F. ; Sanchez, Kyle

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.

项与 Uprosertib 相关的新闻（医药）

2026-02-12

·今日头条

细菌群体感应分子无需菌群介导，直接诱导结肠炎癌变 | 热心肠日报

该篇日报由R·base创作生成，人工审核校对。细菌群体感应如何诱导结肠炎癌变？ Gastroenterology——[25.1] ① 背景与设计：针对细菌群体感应分子（QSM）在溃疡性结肠炎（UC）癌变中的作用不明问题，利用UC患者血清、AOM-DSS小鼠及无菌小鼠模型解析了其致癌机制。② 核心发现与意义：细菌信号分子scAHLs在长病程UC患者中显著升高，并通过重塑肠道微生态及直接激活上皮细胞炎症通路的双重机制，驱动结肠癌发生。③ 临床关联：临床队列分析显示，血清中的细菌群体感应分子短链N-酰基高丝氨酸内酯（scAHLs）及AI-2水平，与UC患者病程（≥10年）及炎症活动度呈显著正相关，是潜在风险标志物。④ 菌群依赖性机制：在结肠炎癌变小鼠模型中，腹腔注射C6-scAHL显著增加了肿瘤负荷与异型增生，伴随拟杆菌门丰度增加及次级胆汁酸等促炎代谢物富集。⑤ 直接宿主作用：无菌小鼠及类器官实验证实，C6-scAHL无需菌群参与即可直接作用于上皮细胞，显著诱导CXCL5、LIF等非经典NF-κB依赖性促癌因子的分泌。原文信息 ▼ Quorum sensing molecules are elevated in long-standing ulcerative colitis and are linked to the development of colitis-associated cancer 2026-02-11 , doi: 10.1053/j.gastro.2026.01.023 上海十院刘占举/康登峰等：FXR抑制中性粒细胞糖酵解，改善肠道炎症 MedComm——[10.7] ① 背景与设计：针对IBD中性粒细胞过度活化机制不明的问题，结合临床活检、Fxr-/-小鼠结肠炎模型及过继转移技术，探究胆汁酸受体FXR的免疫调节功能。② 核心发现：中性粒细胞内源性FXR缺失解除了对mTORC1-糖酵解通路的抑制，导致代谢重编程并驱动促炎表型，加剧肠道黏膜免疫损伤。③ 临床关联与表型：活动期IBD患者中性粒细胞FXR表达显著下调且与疾病严重度呈负相关；Fxr-/-小鼠在DSS诱导或鼠柠檬酸杆菌感染下均表现为结肠炎加重及中性粒细胞胞外诱捕网（NET）形成增多。④ 代谢机制：转录组与代谢流分析证实，FXR缺失导致中性粒细胞糖酵解通量及mTORC1信号显著上调，驱动ROS产生、脱颗粒及迁移能力增强。⑤ 干预与治疗：抑制mTORC1或糖酵解可逆转Fxr-/-中性粒细胞的高炎状态；FXR激动剂INT-747减轻小鼠结肠炎，且在体外抑制mTORC1-糖酵解通路介导的IBD患者中性粒细胞炎症反应。原文信息 ▼ Dysregulation of Farnesoid X Receptor on Neutrophil Homeostasis Exacerbates Intestinal Inflammation via the mTORC1-Glycolysis Signaling Pathway 2026-02-08 , doi: 10.1002/mco2.70637 重医附一院周洁团队：ILC2存活的关键开关，GPX4依赖性铁死亡调控肠炎 Cellular and Molecular Immunology——[19.8] ① 研究背景与设计：针对2型固有淋巴细胞（ILC2）稳态调控机制不清的问题，利用ILC2特异性Gpx4敲除小鼠、DSS结肠炎模型及IBD患者样本，探究铁死亡的作用。② 核心发现：Gpx4依赖性铁死亡构成ILC2存活的关键检查点，该通路在维持肠道黏膜稳态及限制结肠炎进展中起决定性作用。③ 铁死亡易感性：小鼠单细胞测序与流式分析显示，ILC2高表达铁死亡相关基因，并伴随脂质过氧化物堆积，对铁死亡诱导剂高度敏感。④ GPX4功能：条件性敲除Gpx4导致小鼠ILC2发生铁死亡、数量与细胞因子（IL-5/IL-13）产生减少，加重DSS诱导的结肠炎病理损伤。⑤ 分子机制：IFN-γ信号通过其受体IFNGR1增强氧化应激，在缺乏GPX4保护时直接驱动ILC2发生铁死亡。⑥ 硒干预与临床关联：膳食补充硒（Se-Met）可上调GPX4表达，减轻ILC2铁死亡，缓解结肠炎；IBD患者ILC2中GPX4表达降低且脂质过氧化增加。原文信息 ▼ GPX4-dependent ferroptosis governs ILC2 homeostasis and colitis progression 2026-02-09 , doi: 10.1038/s41423-026-01388-w 武大黄翠团队：可"贴壁"的工程益生菌，克服定植难题修复牙周炎 International journal of oral science——[12.2] ① 背景与设计：针对牙周炎氧化应激微环境限制益生菌定植的难题，利用苯硼酸-多巴胺-透明质酸偶联物构建ROS响应性工程化罗伊氏乳杆菌（LR@PDH）。② 核心发现：LR@PDH具备“按需清除ROS”与“炎症靶向粘附”的双重功能，显著逆转大鼠牙周炎模型的牙槽骨吸收并重塑龈下菌群稳态。③ 智能响应机制：高水平活性氧诱导聚合物涂层的苯硼酸酯键断裂，消耗环境中的H2O2并暴露多巴胺儿茶酚基团，从而特异性增强细菌在炎症组织的滞留。④ 生物膜渗透：共聚焦显微镜证实，LR@PDH能穿透由牙龈卟啉单胞菌和具核梭杆菌构成的双菌种生物膜深层，其代谢产物能杀伤多种牙周致病菌。⑤ 体内疗效：LR@PDH治疗牙周炎大鼠，降低了龈沟液ROS水平、牙龈出血指数及牙槽骨丧失距离，上调成骨相关因子OPN和OPG表达。⑥ 菌群调控：LR@PDH治疗显著降低了牙龈卟啉单胞菌丰度，富集了Blautia和双歧杆菌属等有益菌属。⑦ 安全性：组织学及血液生化分析证实，LR@PDH有良好的生物相容性，未对主要器官产生毒副作用，具临床转化潜力。原文信息 ▼ Engineered Lactobacillus reuteri for scavenging reactive oxygen species and modulating oral microflora in periodontitis therapy 2026-02-10 , doi: 10.1038/s41368-025-00418-z NC：膳食植酸是HDAC3的生理"开关"，可修复肠道屏障 Nature Communications——[15.7] ① 研究背景与模型：针对泛HDAC抑制剂由于缺乏特异性常导致严重肠道毒性的临床问题，本研究利用肠上皮特异性肌醇多磷酸多激酶（IPMK）敲除小鼠及IBD患者样本，解析HDAC3特异性活化的生理机制。② 核心发现与意义：确立了膳食来源的植酸（InsP6）为HDAC3的关键生理激活剂，揭示了膳食-表观遗传-肠道稳态轴调控机制，提出口服植酸可作为非免疫抑制策略治疗IBD。③ 激酶依赖性调控：生化分析证实，IPMK的激酶活性而非物理互作决定HDAC3酶活性；IPMK缺失导致细胞内InsP6耗竭，引发H3K9/27及H4K16高乙酰化。④ 变构激活机制：体外重组实验显示，生理浓度InsP6（>10 nM）作为分子胶募集NCOR2的DAD结构域与染色质结合的HDAC3互作，从而变构激活其去乙酰化功能。⑤ 转录抑制靶点：ChIP-qPCR证实，IPMK-HDAC3轴功能缺失导致MMP13等基质金属蛋白酶（MMP）启动子区H4K16乙酰化富集，驱动MMP转录上调并降解紧密连接蛋白ZO-1。⑥ 干预效果：在IPMK敲除及DSS诱导结肠炎小鼠中，口服InsP6显著恢复了肠上皮HDAC3活性，抑制MMP表达并修复肠道通透性缺陷。原文信息 ▼ Phytic acid (InsP6) activates HDAC3 epigenetic axis to maintain intestinal barrier function 2026-02-09 , doi: 10.1038/s41467-026-68994-0 西班牙裔IBD基因组图谱：当欧洲基因无法解释所有风险 Gastroenterology——[25.1] ① 背景与设计：针对美国西班牙裔人群复杂的遗传混合背景，利用全基因组测序及局部祖先感知回归模型分析了7274例样本的IBD遗传结构。② 核心发现：揭示了非洲（AFR）及美洲原住民（AIAN）祖先特异性的独立风险位点，并证实经典风险基因NOD2和IL23R主要由欧洲（EUR）祖先单倍型驱动。③ 表型关联：AFR祖先成分升高与穿透性克罗恩病、肛周病变及手术风险显著相关，AIAN成分升高则显著关联结肠型克罗恩病。④ 新颖位点：鉴定出14个非欧洲祖先特异性风险位点，其中AFR特异性的PCGEM1及TYROBP/LRFN3变异在独立队列中成功验证。⑤ 跨种族复现：发现AIAN特异性的GAD2变异显著增加克罗恩病风险，该位点效应在东亚人群中显示出可转移性。⑥ 临床意义：祖先特异性遗传变异解释了部分临床表型的异质性，提示精准治疗需考量IL23R等靶点在不同祖先背景下的效应差异。原文信息 ▼ Genomic Insights Into Inflammatory Bowel Disease in United States Hispanic Participants: An Ancestry-Focused Study 2026-02-09 , doi: 10.1053/j.gastro.2025.11.007 西湖大学郑钜圣/付元庆等：多模态数据+AI，开启精准营养新纪元（综述） Advanced Science——[14.1] ① AI驱动精准营养：本文提出人工智能（AI）与多模态数据集成是破解个体代谢异质性的核心路径，通过整合基因组、肠道微生物组及脑连接组实现个性化饮食决策优化。② 代谢异质性来源：淀粉酶（AMY1）基因拷贝数、菌群构成及大脑功能架构的生物独特性，导致个体对同类食物反应迥异，揭示了传统“一刀切”膳食指南的局限性。③ 宿主基因组交互：基因变异显著影响营养素利用效率，如载脂蛋白E（APOE）变异调控地中海饮食对血脂的影响，利用多基因评分可精准预测干预后的胆固醇变化轨迹。④ 肠道微生物调控：肠道菌群作为代谢核心接口，其gbu基因簇介导红肉代谢产物氧化三甲胺（TMAO）生成，结合AI预测模型可识别高风险个体并实施针对性干预。⑤ 脑连接组与决策：眶额叶皮层等区域的神经连接模式决定了个体食欲和奖励感，AI分析影像数据可识别特定代谢轨迹，指导预防肥胖及神经退行性疾病。⑥ AI模型整合数据：深度学习模型如phyLoSTM或METRIC能有效纠正膳食调查的自我报告偏差，并生成MODERN评分等客观方案，系统性提升了营养评估的科学性。⑦ N-of-1试验建模：单受试者试验（n-of-1试验）通过个体内部重复测量建立个性化血糖敏感性指数（PGS），排除群体混杂因素，实现从均值模型向生物独特性的跨越。⑧ 挑战与未来转化：面对模型可解释性等瓶颈，未来需通过迁移学习与传感器监测构建数字孪生，推动精准营养从实验室数据向临床应用落地。原文信息 ▼ Advancing Precision Nutrition Through Multimodal Data and Artificial Intelligence 2026-02-11 , doi: 10.1002/advs.202521111 北大肿瘤医院顾晋团队：AKT3重塑微环境驱动结直肠癌卵巢转移 Cancer Research——[16.6] ① 背景与设计：针对结直肠癌卵巢转移（CROM）机制不明的临床问题，整合35例患者单细胞转录组图谱、患者来源类器官（PDO）及小鼠模型解析其分子机制。② 核心发现：揭示AKT3驱动的上皮-间质转化（EMT）样细胞为CROM起始亚群，通过与成纤维细胞（CAF）互作重塑微环境，确立AKT3为关键治疗靶点。③ 细胞亚群特征：高表达AKT3的EMT样上皮细胞特异性富集于原发灶侵袭前沿，该亚群丰度与远处转移发生及患者不良预后显著正相关。④ 分子机制：AKT3过表达直接驱动肿瘤细胞获得侵袭性表型；敲低AKT3或使用Uprosertib处理显著抑制PDO生长及小鼠卵巢定植。⑤ 微环境重塑：原发灶中EMT样细胞通过ITGB1-胶原/纤连蛋白轴响应CAF信号；转移灶中PEG3+/C7+ CAF通过代谢重编程及免疫抑制协助定植。⑥ 空间病理：AKT3+/SNAIL+/ITGB1+肿瘤细胞簇在侵袭前沿被α-SMA+ CAF物理包裹，证实了两者在空间上的协同互作。原文信息 ▼ AKT3-Driven Epithelial-Mesenchymal Plasticity Governs Ovarian Metastasis in Colorectal Cancer via Tumor Microenvironment Remodeling 2026-02-09 , doi: 10.1158/0008-5472.CAN-25-1718 上海交大沈键锋团队：ARID1A兼职异染色质守门人，缺失引发病毒拟态增敏结肠癌免疫 Cancer Research——[16.6] ① 背景与设计：针对结肠癌免疫治疗响应差异，利用蛋白质质谱及多组学分析揭示ARID1A的非经典抑癌机制。② 核心发现：ARID1A行使独立于SWI/SNF复合物的“异染色质守门人”功能，通过维持TRIM28-SETDB1互作抑制病毒拟态。③ 分子机制：ARID1A缺失导致SETDB1从TRIM28解离，特异性引发卫星序列和内源性逆转录病毒（ERVs）去抑制。④ 免疫激活：异常转录产物激活胞质核酸感受器（需cGAS/STING与RIG-I/MDA5协同），诱导I型干扰素反应及CD8+ T细胞浸润。⑤ 临床关联：无论微卫星状态（MSS或MSI），ARID1A功能缺失均能通过病毒拟态增强肿瘤免疫原性。⑥ 转化意义：合成肽阻断ARID1A-TRIM28互作可重塑“冷肿瘤”微环境，显著增强PD-1阻断治疗的抗肿瘤疗效。原文信息 ▼ ARID1A Mediates SWI/SNF-Independent Maintenance of Heterochromatin Architecture to Restrain Viral Mimicry and Immunogenicity in Colon Cancer 2026-02-09 , doi: 10.1158/0008-5472.CAN-25-3231 上海交大杨正峰团队：GPR15空间重分布调控肠癌NAD代谢，增效5-FU化疗 Cancer Research——[16.6] ① 背景与设计：针对结直肠癌中G蛋白偶联受体GPR15表达下调与预后不良的相关性，利用多组学、患者来源类器官（PDO）及异种移植模型（PDX）探究其对化疗敏感性的调控机制。② 核心发现与意义：发现高尔基体驻留的GPR15经应激诱导发生亚细胞重分布，通过空间特异性调控NAD+通量重塑碳中心代谢以增强5-FU的化疗疗效，揭示了GPCR空间信号作为代谢干预靶点的潜力。③ 高尔基体NAD+积累：5-FU处理驱动GPR15与高尔基体定位的PARP4结合并抑制其单ADP核糖基化活性，阻断NAD+消耗从而导致胞质NAD+显著积累。④ 线粒体代谢重编程：GPR15在Gαq与MGST1协助下转位至线粒体，提升线粒体NAD+水平并激活丝氨酸-一碳代谢及嘌呤合成，导致代谢合成致死。⑤ 临床转化策略：临床药物Rucaparib（PARP抑制剂）通过模拟GPR15介导的代谢重编程，在PDO及PDX模型中协同增强5-FU的抗肿瘤活性，有效克服化疗耐药。原文信息 ▼ Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU Chemosensitivity in Colorectal Cancer 2026-02-09 , doi: 10.1158/0008-5472.CAN-25-2586 NC：NAD合成不全是帮凶，NAPRT代谢通路可做肠癌"防火墙" Nature Communications——[15.7] ① 背景设计：针对脱酰胺化NAD合成在哺乳动物中的生理功能不明，利用CRISPR生成的烟酸磷酸核糖转移酶（Naprt）缺陷小鼠、肠道类器官及临床数据库探究其在肠道稳态中的作用。② 核心发现与意义：生理水平的NAPRT通过维持肠上皮细胞NAD池支持DNA修复并抑制肿瘤发生，证实该通路是肠道抗压韧性的关键决定因素。③ 空间表达特异性：单细胞测序显示Naprt选择性富集于肠上皮细胞，而促炎的Nampt则在免疫细胞中广泛表达。④ DNA修复机制：Naprt缺失显著损害应激状态下脱酰胺化NAD合成，通过降低PARP1活化及其驱动的组蛋白ADP-核糖基化水平导致DNA修复受损。⑤ 病理表型表现：Naprt缺失显著增强小鼠对DSS诱导结肠炎的敏感性，并导致AOM/DSS模型及Apcmin/+模型中肿瘤负荷显著增加。⑥ 临床关联性：多癌种转录组数据显示低NAPRT表达与不良预后及肠道代谢功能障碍显著相关。原文信息 ▼ NAPRT-mediated deamidated NAD biosynthesis enhances colon tissue resiliency and suppresses tumorigenesis 2026-02-10 , doi: 10.1038/s41467-026-68998-w 阻断脂肪酸合成酶可破坏癌细胞DNA修复，增效肠癌化疗 Cancer Research——[16.6] ① 背景与设计：针对结直肠癌化疗耐药及复发难题，结合患者窗口试验、类器官及小鼠模型，探究脂肪酸合成酶（FASN）抑制剂TVB-2640联合化疗的增敏机制。② 核心发现：FASN抑制剂导致肿瘤细胞乙酰辅酶A累积，诱发ATM过度乙酰化及随后的泛素化降解，从而阻断DNA损伤修复并增效化疗。③ 临床证据：窗口试验显示，FASN抑制剂TVB-2640处理后患者血浆丙二酰肉碱升高，肿瘤组织中γ-H2AX水平增加且ATM与BRCA1表达显著下调。④ 分子机制：FASN抑制致使胞内乙酰辅酶A池扩增，引起染色质组蛋白及ATM高乙酰化，后者经泛素-蛋白酶体途径降解，破坏同源重组修复信号轴。⑤ 转化意义：在人源肿瘤异种移植模型中，FASN抑制剂联合伊立替康显著抑制肿瘤生长，后续联用奥拉帕利维持治疗进一步延迟了肿瘤复发。原文信息 ▼ FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response 2026-02-09 , doi: 10.1158/0008-5472.CAN-25-1917

微生物疗法临床研究

2025-07-31

·ryvu.com

Ryvu announces publication of novel target discovery data in colorectal cancer from the ONCO Prime platform - RYVU

Krakow, Poland – July 31, 2025 – Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focused on novel therapies targeting emerging oncology indications, announces the publication of data from its proprietary ONCO Prime target discovery platform in the peer-reviewed Scientific Reports journal, part of Nature Portfolio. The manuscript is entitled “Integrated transcriptomic and functional modeling reveals AKT and mTOR synergy in colorectal cancer” and is now available online on the Scientific Reports Krzysztof Brzozka, PhD, Chief Scientific Officer of Ryvu Therapeutics, said: We are honored to have data from our ONCO Prime platform published and reviewed by expert peers in Nature Scientific Reports. The manuscript highlights the unique potential of our patient-derived primary cell cultures to reflect more accurately the complexity of patient tumors and therefore act as an ideal medium for novel therapeutic target discovery. The publication on AKT and mTOR synergy in colorectal cancer is just one example of the broad potential of the ONCO Prime platform across multiple tumor types as we continue to expand the platform. The publication focuses on the discovery of a synergistic therapeutic relationship between mTOR inhibition and AKT inhibition in colorectal cancer cells as one example of the potential of the ONCO Prime platform. Ryvu developed a drug discovery platform using patient-derived primary CRC cultures. Importantly, Ryvu’s engineered model and patient-derived cells reflect the complexity and heterogeneity of primary tumors, not observed with standard immortalized cell lines. High-throughput screening (HTS) of 4255 compounds identified 33 with selective efficacy against CRC cells, sparing normal, healthy epithelial cells. Among the tested combinations, everolimus (mTOR inhibitor) and uprosertib (AKT inhibitor) demonstrated promising synergy with favorable therapeutic window. This synergy might have been overlooked in traditional immortalized cell lines, highlighting the translational advantage of patient-derived systems. The integration of machine learning into the HTS pipeline significantly improved scalability, cost-efficiency, and predictive accuracy. These findings underscore the potential of patient-derived materials combined with machine learning-enhanced drug discovery to advance personalized therapies. Specifically, mTOR-AKT inhibition emerges as a promising strategy for CRC treatment, paving the way for more effective and targeted therapeutic approaches. Beyond the results published in this manuscript, the ONCO Prime platform has already led to the discovery of several other novel targets with therapeutic potential in CRC. These undisclosed, potential novel targets are currently being advanced through the drug discovery process at Ryvu. In addition, the ONCO Prime platform is expanding to other tumor types. Scientific Reports is a peer-reviewed, open-access journal, part of Nature Portfolio, publishing original research across the natural sciences, psychology, medicine and engineering. From nature.com: “Scientific Reports is the 5th most-cited journal in the world, with more than 734,000 citations in 2023, and receives widespread attention in policy documents and the media.” Project is co-financed by the European Union under the Operational Programme European Funds for Modern Economy 2021-2027. Project title: “ONCO Prime: new possibilities for personalised anti-cancer therapy based on patient-derived primary cell cultures, omics characterisation, and functional assays”. Grant Agreement no: FENG.01.01-IP.02-0095/23.

2025-05-30

·摩熵医药

5款MEK抑制剂上市，复星医药、百济领衔，20+在路上

注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需要得到授权。5月29日，复星医药的1类创新药芦沃美替尼（FCN-159，商品名：复迈宁）获批上市，适用于朗格汉斯细胞组织细胞增生症（LCH）和组织细胞肿瘤成人患者；2岁及2岁以上伴有症状、无法手术的丛状神经纤维瘤（PN）的I型神经纤维瘤病（NF1）儿童及青少年患者。芦沃美替尼基本信息图片来源：摩熵医药全球药物研发数据库说到I型神经纤维瘤病（NF1），这是一种较为常见的常染色体显性遗传性疾病。在神经纤维瘤病的三种主要临床类型中，它占据了96%的比例，且已被纳入国家罕见病目录，全球发病率为1/2500-1/3000。大约30%-50%的NF1患者会出现丛状神经纤维瘤（PN），这种瘤体沿神经长轴呈弥漫性生长，常累及多条神经干、分支及神经丛，并侵及周围组织，从而引发毁容、疼痛、运动及呼吸功能障碍、视力受损以及膀胱或肠道功能障碍等一系列严重问题。鉴于NF1相关PN瘤体复杂的生长特性和侵入性生长方式，手术治疗面临着诸多挑战。瘤体往往生长于头部、颈部、脊椎等特殊部位，致使手术风险巨大、难度极高，部分瘤体无法被完全切除，且复发率居高不下，这使得手术治疗效果极为有限，因此，研发有效的治疗药物迫在眉睫。FCN-159作为复星医药开发的高活性、高选择性MEK1/2抑制剂，其作用机制至关重要。MEK是细胞外信号相关激酶（ERK）通路的上游调节因子，通过抑制MEK的活性，能够有效抑制RAS调节RAF/MEK/ERK通路的活性，进而抑制肿瘤生长。而在NF1中，RAS-丝裂原活化蛋白激酶（RAS-MAPK）通路常常发生异常，这种异常会促使细胞增殖和肿瘤沿神经生长，因此，MEK被认为是F1相关PN药物开发的潜力靶点。MEK 抑制剂的应用不仅局限于治疗NF1相关 PN，它还在黑色素瘤、结直肠癌、淋巴瘤等肿瘤的治疗领域展现出巨大潜力。据摩熵医药数据库显示，目前国内已批准5款MEK抑制剂，除了芦沃美替尼，还有诺华/百济神州的Trametinib（曲美替尼）、阿斯利康/默克的Selumetinib（氢司美替尼）、泽璟生物的Donafenibtosylate（甲苯磺酸多纳非尼）和科州制药的Tunlametinib（妥拉美替尼）。国内获批上市的MEK抑制剂图片来源：摩熵医药全球药物研发数据库此外，国内还有20余款MEK抑制剂正处于研发阶段，如卫材的E-6201（II期临床）、恒瑞医药的SHR7390（I期临床）、基石药业的CS3006（I期临床）、正大天晴的TQ-B3234（I期临床）、来凯医药的GSK-795（I期临床）、璧辰医药的ABM-168（I期临床）等。此次11款创新药集中获批，既是中国药审改革成果的集中体现，也标志着本土药企在肿瘤、罕见病等高壁垒领域实现技术突破。随着政策支持力度加大和研发体系完善，未来将有更多创新药进入临床，为患者带来生命希望。END本文为原创文章，转载请留言获取授权近期热门资源获取数据透视：中药创新药、经典验方、改良型新药、同名同方的申报、获批、销售情况-2025042023H2-2024H1中国药品分析报告-2025042024年中国1类新药靶点白皮书-202503中国AI医疗健康企业创新发展百强榜单-202502解码护肤抗衰：消费偏好洞察与市场格局分析-2025022024年FDA批准上市的新药分析报告-2025012024年NMPA批准上市的新药分析报告-2025012024年医保谈判及市场分析报告-2025.012024年中国医疗健康投融资全景洞察报告-202501小分子化药白皮书（上）-2025012024医美注射材料市场发展分析报告-202412中国放射性药物产业白皮书-202410近期更多摩熵咨询热门报告，识别下方二维码领取联系我们，体验摩熵医药更多专业服务会议合作园区服务数据库咨询定制服务媒体合作点击上方图片，即可开启摩熵化学数据查询点击阅读原文，申请摩熵医药企业版免费试用！

上市批准临床2期临床1期申请上市

100 项与 Uprosertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10674	-	-	DB11969

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
葡萄膜黑色素瘤	临床2期	美国	National Cancer Institute	2013-11-21
葡萄膜黑色素瘤	临床2期	法国	National Cancer Institute	2013-11-21
葡萄膜黑色素瘤	临床2期	英国	National Cancer Institute	2013-11-21
复发性浆细胞骨髓瘤	临床2期	加拿大	National Cancer Institute	2013-10-30
难治性多发性骨髓瘤	临床2期	加拿大	National Cancer Institute	2013-10-30
复发性多发性骨髓瘤	临床2期	加拿大	National Cancer Institute	2013-10-30
BRAF V600E突变结直肠癌	临床2期	美国	GSK Plc	2013-10-08
BRAF V600E突变结直肠癌	临床2期	美国	Novartis Pharmaceuticals Corp.	2013-10-08
血液肿瘤	临床2期	美国	GSK Plc	2013-10-08
血液肿瘤	临床2期	美国	Novartis Pharmaceuticals Corp.	2013-10-08

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01902173 (SWOG S1221, CTgov)	临床1/2期	局部晚期恶性实体瘤 \| 转移性实体瘤 \| 皮肤黑色素瘤 ... 更多	27	dabrafenib+GSK2141795 (Phase 1 Doublet Regimen)	製餘襯構遞鏇齋遞觸獵 = 遞鹹膚築觸齋選願製鑰顧積遞糧簾製鹽顧範築 (顧網壓衊鑰夢窪憲繭膚, 築範艱鹽鏇積顧鹽鹹選 ~ 構夢遞夢觸鏇築繭鏇觸)	-	2020-10-14
NCT01902173 (SWOG S1221, CTgov)	临床1/2期	局部晚期恶性实体瘤 \| 转移性实体瘤 \| 皮肤黑色素瘤 ... 更多	27	dabrafenib+trametinib+GSK2141795 (Phase 1 Triplet Regimen)	製餘襯構遞鏇齋遞觸獵 = 廠夢齋顧窪獵鑰築蓋鹹餘選蓋蓋獵襯製夢鬱鹽 (齋夢襯鏇遞餘範網製鹹, 鏇艱願鹽鬱願繭齋夢鑰 ~ 觸糧製窪獵壓獵製築餘)	-	2020-10-14
NCT01138085 (Pubmed) 人工标引	临床1期	实体瘤	126	uprosertib+trametinib	糧醖構網夢範醖窪築網(醖壓製廠醖鬱廠選膚鹹) = Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. 範醖遞鑰齋廠遞鬱鑰艱 (網膚構糧願艱廠網廠積 )	不佳	2020-04-01
NCT01964924 (CTgov)	临床2期	复发性乳腺癌 \| 转移性乳腺癌 \| 浸润性乳腺癌 ... 更多	37	Laboratory Biomarker Analysis+Akt Inhibitor GSK2141795+Trametinib	獵鑰衊願觸鏇製範窪蓋 = 糧網繭糧鹽憲壓觸壓壓鑰醖鬱遞鬱鹹鏇膚繭餘 (顧襯廠選膚蓋願膚鹹觸, 壓醖遞淵鑰蓋鏇齋憲鹹 ~ 糧餘積壓製繭觸製鹽艱) 更多	-	2019-09-20
NCT01907815 (Pubmed \| Clin Lymphoma Myeloma Leuk) 人工标引	临床2期	急性髓性白血病 RAS Mutation	23	Trametinib+GSK2141795	蓋夢觸襯憲遞廠構醖簾(餘醖鬱窪廠醖餘範選齋) = No complete remissions were identified in either cohort 簾醖壓鹽醖範網觸廠鹹 (構鏇蓋鏇網窪壓糧廠糧 ) 更多	积极	2019-07-01
NCT01958112 (Pubmed \| Obstet Gynecol Surv) 人工标引	临床2期	宫颈癌 PI3K \| RAS	14	trametinib+GSK2141795	觸構範選積網範廠壓範(襯網鬱選糧簾廠繭製觸) = 醖淵鬱觸蓋鹽顧鹹遞蓋糧積製夢襯壓築鏇網網 (襯衊膚獵壓艱積觸醖憲 ) 更多	不佳	2019-07-01
NCT01958112 (CTgov)	临床2期	复发性宫颈癌	14	GSK1120212 (trametinib)+GSK2141795	網遞積衊糧選網積築衊(網夢淵願築壓範廠艱願) = 製衊蓋餘築製糧鬱選鬱醖窪鑰鏇壓鹽觸膚製夢 (鬱膚選餘顧廠鹽衊築網, 憲餘齋繭鬱餘顧獵夢艱 ~ 構獵窪廠築憲襯淵廠淵) 更多	-	2019-01-02
NCT00920257 (Pubmed \| Invest New Drugs) 人工标引	临床1期	实体瘤	77	GSK2141795	簾獵網繭顧構蓋遞鏇糧(觸製繭餘範築鏇簾鬱製) = 選製襯遞壓醖齋鹽觸鹹鹽選簾範鹹齋願艱範範 (觸簾蓋淵鑰壓鏇網構淵 ) 更多	积极	2018-12-01
NCT01907815 (CTgov)	临床2期	成人急性髓性白血病	24	GSK2141795+Trametinib (Trametinib 2.0 mg + GSK2141795 25 mg)	鏇鏇顧簾夢憲製選蓋網 = 夢壓廠壓遞網觸鹽願憲壓艱觸範觸選鹽艱糧願 (積膚顧願襯夢觸齋鹹壓, 夢鏇簾簾簾觸繭蓋遞憲 ~ 壓蓋蓋憲顧網艱遞淵窪) 更多	-	2018-04-06
NCT01907815 (CTgov)	临床2期	成人急性髓性白血病	24	GSK2141795+Trametinib (Trametinib 1.5 mg + GSK2141795 50 mg)	鏇鏇顧簾夢憲製選蓋網 = 壓鹹鏇蓋襯繭願廠鬱衊壓艱觸範觸選鹽艱糧願 (積膚顧願襯夢觸齋鹹壓, 願衊餘夢醖觸壓範構鬱 ~ 衊窪製醖鏇糧繭築壓積) 更多	-	2018-04-06
NCT01941927 (Pubmed \| Pigment Cell Melanoma Res) 人工标引	临床2期	NRAS突变黑色素瘤 NRAS Mutation \| BRAF Wild-type \| NRAS Wild-type	20	trametinib+GSK2141795 (NRAS-mutant patients)	衊壓餘繭構鏇鹽製醖築(製選願蓋顧淵遞壓鹹壓) = No objective responses were noted in either cohort. 艱夢願糧遞齋齋壓顧範 (壓醖願艱鏇網憲鏇繭鹽 ) 更多	不佳	2018-01-01
NCT01941927 (Pubmed \| Pigment Cell Melanoma Res) 人工标引	临床2期	NRAS突变黑色素瘤 NRAS Mutation \| BRAF Wild-type \| NRAS Wild-type	20	trametinib+GSK2141795 (BRAFWT NRASWT patients)		不佳	2018-01-01
NCT01902173 (SWOG S1221, ASCO 12017 \| ASCO 22017) 人工标引	临床1期	BRAF突变实体瘤 BRAF V600 mutant	19	dabrafenib+GSK2141795	鏇簾鹹壓獵鬱廠襯觸壓(壓遞醖糧鏇糧艱繭餘糧) = At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash 餘簾艱願築鑰廠餘願網 (憲醖觸選艱積觸遞衊鏇 )	积极	2017-06-05
NCT01902173 (SWOG S1221, ASCO 12017 \| ASCO 22017) 人工标引	临床1期	BRAF突变实体瘤 BRAF V600 mutant	19	dabrafenib+trametinib+GSK2141795		积极	2017-06-05