VT-3989

STOCKHOLM, Feb. 14, 2024 /PRNewswire/ -- Beactica Therapeutics AB, the Swedish precision oncology company, today announced that its TEAD programme has been selected for a late-breaking presentation at the American Association for Cancer Research's Annual Meeting 2024. The conference will take place on April 5-10, 2024 in San Diego, California. Dr Peter Brandt, Head of Chemistry, will present a poster entitled Degraders of TEAD transcription factors based on interface 3 binders on Sunday April 7, 2024, at 1:30 PM – 5:00 PM. The location is at the San Diego Convention Center, Section 52, abstract presentation number: LB029. The session title is Late-Breaking Research: Chemistry. The presentation will include new positive results from studies with novel proteolysis-targeting degraders of TEAD based on interface 3-binding ligands under development by Beactica. This will include head-to-head in vitro comparisons with other classes of TEAD modulators in clinical development such as palmitoylation inhibitors and direct YAP–TEAD protein–protein interaction inhibitors. The work to be presented contains contributions by Beactica's collaborators at the National Center for Advancing Translational Sciences (NCATS), one of 27 institutes and centers at the U.S. National Institutes of Health (NIH). Organised by the American Association for Cancer Research, the AACR Annual Meeting is the largest and most important cancer drug discovery event in the world. It has an anticipated attendance of more than 20 000 scientists, clinicians, advocates, and other attendees. The event spans integrative cancer science, global impact, individualised patient care and showcases the best and most up-to-date cancer science available. About TEAD TEAD 1–4 (Transcriptional Enhanced Associate Domain) are transcription factors that together with its coactivators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) play key roles in the Hippo signalling pathway that regulates 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 achieved with the TEAD inhibitor VT3989 and 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 . Beactica Therapeutics Contact Per Källblad M.Sc. Ph.D. CEO [email protected] Tel: +46 18 56 08 80 The following files are available for download: SOURCE Beactica Therapeutics AB

关注并星标CPHI制药在线Hippo信号通路是最早在黑腹果蝇中发现的一条与发育相关的信号通路，在多种生物体中通过调控细胞增殖、凋亡、干细胞自我更新，参与组织发育、组织稳态维持以及再生修复等多项生物学功能。       Hippo信号通路由一系列保守的激酶组成，其核心是一个激酶级联反应。Mst1/2（果蝇Hippo的同源物）激酶和SAV1形成一种可磷酸化和激活LATS1/2的复合体。LATS1/2激酶反过来磷酸化并抑制转录共激活因子YAP和TAZ（Hippo通路的两个主要下游效应分子）。去磷酸后，YAP/TAZ转运到胞核，并与TEAD1-4及其他转录因子发生相互作用，从而诱导促进细胞增殖并抑制凋亡的基因表达。       Hippo信号通路包含多种肿瘤抑制基因，其异常和突变会导致下游的原癌基因YAP和TAZ的过度活化，是多种肿瘤主要的致癌驱动因素，并与多种肿瘤耐药机制相关。研究显示，在所有癌症类型中，约10%的患者的Hippo通路中发生了基因改变。       关于TEAD       转录增强相关结构域(TEAD)蛋白是Hippo信号通路的下游效应子，可调节细胞增殖和干细胞功能。不过TEAD无法单独激活转录，需要辅助激活剂（如YAP、TAZ、VgLL和p160蛋白）的帮助。       TEAD蛋白家族包含TEAD1-4共四种转录因子，其转录输出在肿瘤发生发展、迁移、肿瘤代谢、免疫、耐药等过程中起重要作用。研究发现，TEAD蛋白在胃癌、结肠直肠癌、乳腺癌和前列腺癌等多种肿瘤中过表达，且其表达与患者的不良生存率相关。此外，调节TEAD蛋白的表达水平可以控制细胞的增殖和分化，从而实现组织器官的再生。       TEAD靶向药进展       TEAD被认为是肿瘤药研发的潜力靶点，全球药企针对该靶点已研发出多款在研药物，如英矽智能的ISM6331（临床前）、贝达药业的BPI-460372（1期临床）、Vivace Therapeutics的VT3989（1期临床）、诺华的IAG933（1期临床）、Ikena Oncology的IK-930（1期临床）、同源康医药的TY-1054（临床前）、罗氏的GNE-7883（临床前）、勤浩医药的GH658（临床前）。       ISM6331是一款泛TEAD非共价抑制剂，其新颖分子骨架由英矽智能自有生成化学平台Chemistry42生成，具有同类最佳（best-in-class）潜力。临床前研究显示：ISM6331在多个细胞系中展现出广谱抗肿瘤效果，在动物模型中低剂量起效，同时具备良好的口服生物利用度以及较大的安全窗。       BPI-460372是贝达药业自主研发的新型TEAD小分子抑制剂，今年1月先后在国内和美国获批临床。临床前数据显示，BPI-460372可以特异性靶向Hippo信号通路下游的细胞核内转录因子TEAD，抑制下游基因的转录和翻译，从而抑制肿瘤细胞的增殖、生存、分化和迁移。此外，该药在临床前研究中展现出优秀的体外及体内活性、优秀的药代动力学性质及良好的安全性。       VT3989是一种口服、高效、选择性的TEAD棕榈酰化抑制剂，可阻断YAP功能，并显示出良好的临床前活性。该药治疗恶性间皮瘤富集晚期实体瘤及其他具有神经纤维瘤病2(NF2)突变肿瘤的1期临床试验取得积极结果，并亮相2023 AACR。       IK-930是一种新型的TEAD抑制剂，通过与TEAD结合，阻止促进癌症进展的多个基因转录，曾被FDA授予快速通道资格。临床前结果表明，IK-930与奥希替尼联合使用可以增加多种EGFRm肿瘤模型中的细胞凋亡，并改善抗肿瘤活性。2022年10月，Ikena Oncology与阿斯利康达成一项临床试验合作协议，探索奥希替尼联合IK-930治疗EGFR突变非小细胞肺癌（NSCLC）的效果。       TY-1054是同源康医药独立开发的一款新型TEAD小分子抑制剂，拟用于治疗实体瘤。已有研究结果显示，TY-1054在体内外表现出抗肿瘤效应，且具有良好的安全性。       GH658是一款靶向TEAD蛋白棕榈酰化口袋的变构抑制剂。在体外试验中，GH658展现出低纳摩尔级别的TEAD抑制活性及低纳摩尔级别的对NF2缺失的间皮质瘤细胞系的增殖抑制活性。在动物实验中，GH658每天一次给药能够完全抑制NF2突变的CDX模型，并且动物耐受良好，无明显体重下降。此外，GH658对于多种EGFR-RAS信号通路抑制剂的耐药模型展现出较好的体内疗效。而且，GH658在多个种属中均有较好的PK及安全性质。       总结TEAD抑制剂已在多项早期研究中显示出抗肿瘤潜力，但整体来看TEAD抑制剂进展缓慢，最快处于1期临床。我国药企也积极布局TEAD靶点，如贝达药业、英矽智能、同源康医药、勤浩医药。肿瘤药市场巨大，是国内外药企积极布局的热门领域，期待未来TEAD靶点可以早日迎来重大突破。       来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~