GT-02897

近日，标新生物（Gluetacs Therapeutics）联合上海交通大学医学院附属新华医院卢莹课题组等国内研究团队在国际期刊《Nature Communications》在线发表了题为“CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma”的研究论文。该研究发现，细胞周期蛋白依赖性激酶9（CDK9）是T细胞淋巴瘤（TCL）生长的驱动因素。抑制激酶活性、敲除或利用蛋白水解靶向嵌合体（PROTAC）降解CDK9蛋白，均可显著降低体外和小鼠模型中TCL细胞的生长。研究人员合成、优化并筛选出在纳摩尔浓度靶向降解CDK9蛋白并杀伤TCL肿瘤细胞的GT-02897先导化合物。GT-02897与全反式维甲酸（ATRA）联合用药，可在体外和异种移植模型中协同抑制肿瘤生长，为彻底清除TCL提供了一种具有良好临床转化前景的治疗策略。 T细胞淋巴瘤（TCL）是以T淋巴细胞克隆性增殖为特征的一类恶性肿瘤。生物学行为和临床表现呈现高度侵袭性和异质性，缺乏高效、特异的治疗手段。研究团队首选利用小分子化合物库筛选出TCL细胞对CDK9抑制剂高度敏感。进一步，针对CDK9驱动TCL发生发展的机制，团队通过深入细致的研究揭示了CDK9激酶活性以外的新功能，即通过招募E3泛素连接酶HUWE1增强维甲酸受体RARα蛋白K360位点泛素化修饰水平及蛋白酶体途径降解。相应地，利用PROTAC靶向降解CDK9蛋白则能提高RARα蛋白水平，从而赋予肿瘤细胞对RARα配体ATRA的敏感性。基于这一新机制，团队开发了靶向降解CDK9小分子GT-02897联合ATRA的序贯治疗方案，在临床前模型中取得良好疗效。因此，该研究不仅为开发靶向CDK9的治疗策略提供更全面的理论依据，还将拓展诱导分化治疗的效应谱，具有重要的临床转化前景。 该工作是标新生物联合上海交通大学医学院附属新华医院、海南医科大学（海南省医学科学院）、上海科技大学和大连医科大学等多研究团队完成的。本项目获得国家自然科学基金的资助。 标新生物作为通讯单位与学术机构合作再发文章，进一步展示了GlueTacs®平台上丰富的技术储备和转化潜力，也体现出该平台重要的学术价值和商业潜力。 论文链接：   https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/39632829/ Recently, Gluetacs Therapeutics, in collaboration with Lu Ying's research group from the Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine and other domestic research teams, published a research paper titled "CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma" in the international journal Nature Communications. The study discovered that cyclin-dependent kinase 9 (CDK9) is a driving factor in the growth of T-cell lymphoma (TCL). Inhibition of kinase activity, gene knockout, or degradation of CDK9 protein using proteolysis-targeting chimeras (PROTACs) can significantly reduce the growth of TCL cells both in vitro and in mouse models. Researchers synthesized, optimized, and screened a lead compound GT-02897 that targets and degrades CDK9 protein at nanomolar concentrations, killing TCL tumor cells. The combination of GT-02897 with all-trans retinoic acid (ATRA) synergistically inhibits tumor growth in vitro and in xenograft models, providing a therapeutic strategy with promising clinical translation prospects for the complete eradication of TCL. T-cell lymphoma (TCL) is a category of malignant tumors characterized by the clonal proliferation of T-lymphocytes. It exhibits highly aggressive and heterogeneous biological behavior and clinical manifestations, lacking efficient and specific treatment methods. The research team initially used a small molecule compound library to screen for high sensitivity of TCL cells to CDK9 inhibitors. Furthermore, to elucidate the mechanism by which CDK9 drives the development of TCL, the team revealed a novel function of CDK9 beyond its kinase activity, which is to enhance the ubiquitination level and proteasomal degradation of retinoic acid receptor RARα protein at the K360 site by recruiting the E3 ubiquitin ligase HUWE1. Correspondingly, targeting the degradation of CDK9 protein using PROTACs can increase RARα protein levels, thereby endowing tumor cells with sensitivity to RARα ligand ATRA. Based on this new mechanism, the team developed a sequential treatment plan targeting the degradation of CDK9 with the small molecule GT-02897 combined with ATRA, achieving good efficacy in preclinical models. Therefore, this research not only provides a more comprehensive theoretical basis for developing CDK9-targeting therapeutic strategies but also expands the spectrum of effect of differentiation therapy, holding significant potential for clinical translation. This work was completed by Gluetacs in collaboration with multiple research teams, including Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Hainan Medical University (Hainan Province Medical Science Academy), ShanghaiTech University, and Dalian Medical University. The project was funded by the National Natural Science Foundation of China. Gluetacs, as the corresponding unit, has once again published an article in collaboration with academic institutions, further demonstrating the rich technical reserves and translational potential of the GlueTacs®platform, as well as its significant academic and commercial value. 关于标新生物 标新生物（Gluetacs Therapeutics）是一家专注于研发口服蛋白降解小分子药物的生物医药公司，为上海科技大学孵化的首家生物医药公司，成立于2020年2月，2021年3月正式运营，由多名在蛋白降解领域深耕多年的科学家领衔创立。公司拥有自主知识产权的分子胶降解剂（GLUE）和双机制降解剂（GLUETAC）开发平台，并拥有申请和授权不同国家该领域专利近百项，具备独具特色的差异化技术路线和发展战略。公司现已自主建立人工智能虚拟筛选平台、体外药效筛选平台、药代动力学平台、蛋白质组学平台以及肿瘤动物药效模型平台，实现了完备的全流程药物研发体系建设。标新生物自从2021年3月正式运营以来，成功推动两个候选药物进入临床试验，充分验证和体现了GlueTacs®平台快速发现候选药物和管线推进的能力。 标新生物自成立以来受到业内的广泛关注，2024授牌成为全国生物医药企业平台理事单位，2022-2024连续三年获得上海市科技型中小企业称号，2023、2024连续两年入选华医榜中国生物医药科技创新价值榜最具成长性小分子创新药企业TOP10，2023、2024连续两年入选上海市高价值专利运营大赛百强，荣获2024长三角高价值专利运营大赛金奖，荣获2024专精特新中小企业和创新型中小企业称号、2024临港新片区科创新锐企业称号、2024第四届生物医药明日之星大赛入围奖、2023中国海归创业大赛三等奖、2023临港杯第九届创青春上海青年创新创业大赛一等奖、2022浦东新区全球高校校友科创大赛二等奖、2022中国创新制药企业TOP10、2022第十一届中国创新创业大赛成长组全国赛优秀企业奖、2022第6届医疗健康投资卓悦榜年度生物医药最佳企业、2022第五届中国创翼创业创新大赛上海选拔赛浦东赛区十佳创翼奖、2022浦东新区全球高校校友科创大赛二等奖、2022Venture50新芽榜150强、2021年度全国颠覆性技术创新大赛优秀项目、2021年第二届生物产业年度攀登榜年度最具投资潜质的新锐BioTech、2021中国生物医药产业链创新风云榜金马奖最具关注度新锐企业TOP10奖项。公司陆续获得多项科技部和上海市科委资金支持，纳入临港新片区前沿产业优秀人才安家补贴、重点产业人才补贴、人才引进重点机构名单，知识产权管理体系获得中国专利保护协会认证，多位团队核心成员陆续获得临港新片区十大科技创新先锋人物、谈家桢生命科学产业化奖、杨雄科技创业奖、东方英才创业青年领军人才、上海高层次海外人才和上海市浦江人才等称号。公司也先后成为上海科技大学创新型硕士和工程博士培养单位，并先后与十多位海内外专家教授进行科研研究合作。 About Gluetacs Therapeutics Gluetacs Therapeutics, focusing on the development of oral small molecule protein degrader, is the first biotech company incubated from ShanghaiTech University,  Gluetacs was founded in February 2020, and started to operation in March 2021. It was founded by several scientists that have done intensive studies in target protein degradation. The company has independent intellectual property of GLUE degrader and GLUETAC degrader development platform with around 100 patents filed, which has indicated a unique and differentiated technical route and development strategy. The company has established artificial intelligence virtual screening platform, in vitro pharmacodynamics screening platform, pharmacokinetics platform, proteomics platform and in vivo drug pharmacology evaluation platform, and has constructed a complete whole-process drug R&D system. Since its operation in March 2021, Gluetacs Therapeutics has successfully advanced 2 drug candidates into phase I clinical trial, which has demonstrated the GlueTacs® platform's ability to rapidly discover drug candidates and promote pipelines. 长按识别二维码，关注标新 注：转载请注明出处，感谢您对标新生物的关注