The Hippo pathway, a highly conserved growth-inhibitory signaling cascade, critically regulates fundamental processes including development, tissue homeostasis, and tumorigenesis. Its distal effectors, the homologous oncogenic transcriptional coactivators YAP/TAZ, are crucial for cell proliferation, survival, and fate. Frequently upregulated in human cancers, YAP/TAZ drive tumor progression and resistance to chemotherapy/immunotherapy, making them promising therapeutic targets. However, their inherent disordered structures pose challenges for direct targeting. Due to the fact that YAP/TAZ primarily exerts carcinogenic activity by regulating gene expression through binding to TEAD transcription factors, regulating TEADs provides an indirect strategy. Notably, TEADs undergo essential autopalmitoylation, serving as a critical checkpoint that regulates their homeostatic protein levels within cells, while also providing appropriate stability and flexibility for efficient interaction with YAP/TAZ. This post-translational modification can be disrupted by small molecule inhibitors. In this study, a virtual screening of DrugBank database against the TEAD palmitoylation cavity revealed the FDA-approved diuretic drug ethacrynic acid (EA) as a TEAD binder, which was validated by using 1D NMR waterLOGSY, thermal shift assay and isothermal titration calorimetry. Subsequently, we confirmed that EA directly binds to TEAD palmitoylation pocket, inhibiting its palmitoylation, destabilizing TEAD conformation, disrupting YAP-TEAD interaction, and suppressing transcriptional activity. In YAP-activated MDA-MB-231 and NCI-H226 cells, EA downregulates YAP-TEAD target genes (CTGF and CYR61) and inhibits proliferation, colony formation, and migration. These findings establish EA-mediated TEAD suppression as a novel molecular mechanism for its anti-tumor effects. Furthermore, the structure-based optimization of EA yielded novel covalent TEAD inhibitors with enhanced activity. Representative compound EA-C15 covalently binds to the TEAD palmitoylation site, blocks palmitoylation and transcriptional activity, and inhibits NCI-H226 cell proliferation and YAP-TEAD target gene transcription at sub-micromolar concentrations. Collectively, these results establish EA and its derivatives as promising TEAD inhibitors that will provide molecular tools and insights for developing YAP-TEAD-targeted anti-tumor therapies.

2025-09-01·MOLECULAR CELL

Endogenous YAP/TAZ partitioning in TEAD condensates orchestrates the Hippo response

Article

作者: Zhu, Guangya ; Zhao, Zheng ; Chen, Qi ; Tian, Yawen ; He, Hao ; Zhu, Jidong ; Yin, Baobing ; Mi, Ting ; Zhu, Tianxin ; Zhang, Hanxiao ; Li, Huan ; Zhang, Qi ; Lu, Wenchao ; Lu, Jiajun ; Pan, Qiuhui ; Jiang, Hewei ; Cao, Hengyi ; Xie, Lijuan ; Guo, Yan ; Xie, Jingjing ; Sun, Tianyue ; Mao, Siwei ; Li, Lingyu ; Zhu, Ying ; Zhen, Ni

YAP/TAZ are transcriptional co-activators that pair with transcription factor TEA/ATTS domains (TEADs) for modulating the Hippo pathway. Previous works propose the potential role of YAP/TAZ phase separation for transcriptional activation, yet the biomolecular basis of endogenous YAP/TAZ-TEAD condensates remains unclear. Here, we dissect their endogenous morphology, revealing that YAP/TAZ are client proteins recruited to TEAD condensates in various human cell lines. TEAD proteins have robust intrinsic potential to undergo phase separation, and YAP/TAZ condensates disappear immediately after losing their interaction with TEADs. Moreover, TEAD condensates serve as central organizing hubs to dynamically concentrate active YAP and other markers of transcriptional activation. Based on this, we revisited a series of recently characterized TEAD inhibitors and identified that VGLL4 represents a critical regulator assisting TEAD central pocket inhibitors. Altogether, we demonstrate a fundamental role of TEAD condensates in spatially regulating YAP/TAZ signaling, underscoring their significance in further deciphering TEAD biology and applications in TEAD-targeted therapy.

2023-07-03·Nature communications1区 · 综合性期刊

Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens.

1区 · 综合性期刊

ArticleOA

作者: Mourikis, Thanos P ; Altorfer, Marc ; Schmelzle, Tobias ; Gopalakrishnan, Rajaraman ; Sprouffske, Kathleen ; Naumann, Ulrike ; Barbosa, Inês A M ; Knehr, Judith ; Schübeler, Dirk ; Sheng, Caibin ; Golji, Javad ; Lindeman, Alicia ; Lopes, Rui ; Tordella, Luca ; Galli, Giorgio G ; Mercan, Samuele ; Barys, Louise ; Wengert, Simon ; Russ, Carsten ; Martin, Typhaine ; Ji, Fei

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.

项与 TEAD 抑制剂 (Beactica) 相关的新闻（医药）

2025-10-22

·投资观健

2800万美元! 桥济生物完成B+轮融资

近日，桥济生物（BridGene Biosciences, Inc.以下简称 “BridGene”）宣布完成 2800 万美元 B+ 轮融资。本轮融资由康君资本领投，高特佳投资、比邻星创投以及现有投资方龙磐投资和磐谷创投共同参与。本轮融资资金将主要用于推进公司核心候选药物BGC-515 的临床开发。BGC-515 是一款针对实体瘤的共价 TEAD 抑制剂，目前在I期临床，并计划于近期启动 II 期临床研究。此外，资金还将用于推动公司第二个管线项目于 2027 年进入临床阶段，并加速公司在肿瘤及自身免疫疾病领域的后续管线布局。桥济生物2022年成立于江苏苏州，本轮融资也将进一步增强BridGene的战略合作能力，并持续推动其自主研发的IMTAC™(Isobaric Mass-Tagged Affinity Characterization)化学蛋白质组学平台在肿瘤学、免疫学及神经科学等领域的广泛应用潜力。 BridGene Biosciences 联合创始人兼首席执行官曹平博士（Ping Cao, Ph.D.）表示：“本次融资为公司提供了关键资源，以加速推进核心项目BGC-515的临床 II 期开发。这一轮融资不仅将支持更多难成药靶点管线项目进入临床阶段，也将助力我们通过战略合作拓展 IMTAC™ 平台的应用边界，将科学发现真正转化为造福患者的创新疗法。” 康君资本高级合伙人苏跃星表示：“我们非常高兴能够领投 BridGene Biosciences 本轮融资。BridGene 的 IMTAC™ 平台代表了一种强大且差异化的药物发现新模式，使公司能够开发靶向长期以来被视为‘不可成药’的靶点的小分子药物。随着以共价 TEAD 抑制剂 BGC-515 为代表的管线不断推进，以及多个项目在肿瘤与自身免疫等治疗领域的拓展，我们相信 BridGene 具备为患者带来变革性疗法并在生物医药领域创造长期价值的巨大潜力。” -end- 进群、合作、投稿加主编微信

临床1期临床2期引进/卖出

2025-10-20

·BioBAY

桥济生物宣布完成2800万美元 B+ 轮融资，加速临床研发与平台拓展

近日，BioBAY园内企业桥济生物（BridGene Biosciences, Inc.以下简称 “BridGene”）宣布，已于近期完成 2800 万美元 B+ 轮融资。本轮融资由康君资本领投，高特佳投资、比邻星创投以及现有投资方龙磐投资和磐谷创投共同参与。本轮融资资金将主要用于推进公司核心候选药物BGC-515 的临床开发。BGC-515 是一款针对实体瘤的共价 TEAD 抑制剂，目前在I期临床，并计划于近期启动 II 期临床研究。此外，资金还将用于推动公司第二个管线项目于 2027 年进入临床阶段，并加速公司在肿瘤及自身免疫疾病领域的后续管线布局。与此同时，本轮融资也将进一步增强BridGene的战略合作能力，并持续推动其自主研发的IMTAC™(Isobaric Mass-Tagged Affinity Characterization)化学蛋白质组学平台在肿瘤学、免疫学及神经科学等领域的广泛应用潜力。 BridGene Biosciences 联合创始人兼首席执行官曹平博士（Ping Cao, Ph.D.）表示：“本次融资为公司提供了关键资源，以加速推进核心项目BGC-515的临床 II 期开发。这一轮融资不仅将支持更多难成药靶点管线项目进入临床阶段，也将助力我们通过战略合作拓展 IMTAC™ 平台的应用边界，将科学发现真正转化为造福患者的创新疗法。” 康君资本高级合伙人苏跃星表示：“我们非常高兴能够领投 BridGene Biosciences 本轮融资。BridGene 的 IMTAC™ 平台代表了一种强大且差异化的药物发现新模式，使公司能够开发靶向长期以来被视为‘不可成药’的靶点的小分子药物。随着以共价 TEAD 抑制剂 BGC-515 为代表的管线不断推进，以及多个项目在肿瘤与自身免疫等治疗领域的拓展，我们相信 BridGene 具备为患者带来变革性疗法并在生物医药领域创造长期价值的巨大潜力。” 关于 BridGene Biosciences BridGene Biosciences 是一家创新型生物科技公司，致力于发现和开发靶向传统“不可成药”靶点的新型小分子药物。公司自主研发的 IMTAC™（Isobaric Mass-Tagged Affinity Characterization）化学蛋白质组学平台，可在活细胞环境中筛选小分子与全蛋白组的结合，精准识别新型结合位点，从而发现具有高临床价值的候选药物分子。目前，BridGene 拥有多元化的研发管线，其中 BGC-515—— 一款正在针对实体瘤开展临床研究的共价 TEAD 抑制剂——是公司首个进入临床阶段的候选药物，初步验证了 IMTAC™ 平台在“难成药”靶点发现上的强大能力。依托该平台，公司已布局多个肿瘤与自身免疫疾病领域的创新项目。 BridGene 将化学生物学与转化医学相结合，持续开拓新的治疗路径，致力于为全球患者带来变革性的创新疗法。关于康君资本康君投资管理（北京）有限公司成立于2019年，是一家专业的私募股权投资管理机构。康君资本作为康龙化成全球唯一的投资平台，依托康龙化成强大的产业背景，专注于生物医药领域的股权投资。康君资本通过独特的产业视角，关注全球领先的新药研发服务及技术创新平台、生物科技公司、医疗器械公司等，致力于成为生命科学、健康产业和资本的纽带及可信赖的长期合作伙伴。关于高特佳投资 2001年高特佳投资在深圳成立，率先在业内提出“主题行业投资”的投资模式，专注医疗健康产业投资，以战略性股权投资为主导，覆盖VC、PE、Pre-IPO及并购的全投资阶段。拥有国内为数不多的深度聚焦医疗健康赛道的专业投资团队，致力于成为具有全球影响力的医疗健康投资机构。资产管理规模超230亿元人民币，先后投资医疗健康企业超110家，并推动了迈瑞医疗、联影医疗、康方生物等41家企业成功上市。公司业务立足中国面向全球，在深圳、上海、北京、香港等地建立运营中心，致力于在全球范围内投资优秀医疗健康企业，为全球资本和医疗企业开拓发展新机遇，协助创业者成就伟大企业。关于比邻星创投比邻星创投是中国领先的医疗科技投资机构，管理多支人民币及美元基金，专注推动具有全球商业化价值的突破性创新。目前比邻星投资超70家企业、主导设立30余家平台公司，覆盖高端医疗器械、生物技术和生命科学领域。实现60+全球首创产品突破、获40+国际认证、超80%产品完成全球化布局。比邻星以“全面赋能+战略整合”为核心战略，构建国际领先创新生态，持续缔造中国医疗全球化价值标杆。关于磐谷创投磐谷创投自2012年起专注于信息技术、生命科学、人工智能及清洁技术等前沿科技的早期风险投资。目前资产管理规模超过30亿元人民币，累计投资哈啰出行、云知声等50余家企业。我们坚持以深度行业研究和长期协同为核心理念，我们的愿景是助力探索人类文明新疆域。 ▌文章来源：桥济生物责编：何文正审核：任旭推荐阅读瑞金医院临床试验企业开放日圆满举行研发动态丨吉美瑞生全球首创自体肺脏再生细胞药物Ⅱ期临床结果发布，实现肺功能根本性改善 S²CUBE丨瑞士生物科技公司Bright Peak研发蛋白质化学合成技术，精确定制治疗性细胞因子

临床1期临床2期临床3期

2024-05-13

·PRNewswire

Beactica Therapeutics to present breakthrough in YAP-TEAD programme at the Hippo Pathway Drug Development Summit 2023

STOCKHOLM, May 16, 2023 /PRNewswire/ -- Beactica Therapeutics AB, the Swedish precision oncology company, today announced that its YAP-TEAD programme has been selected for an oral presentation at the 2nd Hippo Pathway Targeted Drug Development Summit 2023. The conference will take place on May 23-35, 2023, in Boston, Massachusetts. Dr Peter Brandt, Head of Chemistry, will present a talk entitled Specific Degraders of TEADs Based on Interface 3 Binding on Thursday May 25, 2023, at 2:00 – 2:30 PM in the Boston Park Plaza. The presentation will showcase a breakthrough in the development of novel cell-active targeted degraders of TEAD, with therapeutic potential against multiple types of life-threatening cancers. The degraders developed are based on previously generated proprietary inhibitors of the YAP–TEAD protein–protein interaction. These have now been developed into bifunctional compounds with the additional ability to induce selective degradation of TEAD through the proteasome, the cell's own waste disposal system. The achievement provides a strong validation of the capabilities Beactica has built for targeted protein degradation. Compared to traditional inhibitors, targeted protein degraders have the potential to achieve a more potent and durable therapeutic effect. The Hippo Pathway Targeted Drug Development Summit is the first and only industry-led forum, uniting a community focused on progressing functional understanding, and realizing the potential of the Hippo signaling pathway to enhance the discovery, translation and clinical development of safe and effective drugs in oncology, regenerative medicine and beyond. About YAP–TEAD YAP1 (Yes-associated protein 1) is a coactivator that together with TEAD 1–4 (TEA Domain) transcription factors play key roles in the Hippo signalling pathway that regulate cell proliferation, apoptosis, and stemness. Dysregulation of the Hippo pathway and subsequent activation of TEAD has been reported in a wide range of cancers such as squamous cell carcinoma, head and neck, gynaecological, and gastrointestinal cancers. The first clinical proof-of-concept for drugging the Hippo–YAP–TEAD pathway was recently achieved with the TEAD inhibitor VT3989, which was presented at the American Association for Cancer Research (AACR) Annual Meeting in April 2023. About Beactica Therapeutics Beactica Therapeutics AB is a privately held precision oncology company committed to the fight against cancer. The company is advancing a pipeline of novel small molecule therapeutics with a focus to treat genetically defined cancers with significant unmet medical need. Beactica's approach is centered around targeting synthetically lethal disease proteins with allosteric modulators and targeted protein degraders. Beactica deliver value to patients and shareholders by advancing its programmes to clinical proof of concept. For more information, please visit www.beactica.com.

AACR会议

100 项与 TEAD 抑制剂 (Beactica) 相关的药物交易

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