180055

近日，标新生物（Gluetacs Therapeutics）和上海科技大学范高峰团队在国际知名期刊《Cell Death & Disease》在线发表了题为“Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader”的文章，报道了新一代靶向PARP1蛋白的PROTAC降解剂，抑制PARP1酶活的同时减少了DNA捕获效应，并在BRCA缺陷的肿瘤中展现出安全且有效的抗肿瘤疗效。 图1 聚（ADP-核糖）聚合酶1（PARP1）作为真核细胞内催化多聚（ADP-核糖）基化反应的关键酶，在调控蛋白翻译后修饰中发挥核心作用。PARP1主要参与单链DNA断裂的修复过程。当PARP1功能受损，导致单链DNA损伤无法有效修复，在伴有BRCA基因突变的情况下，同源重组修复途径受阻，进而引发双链DNA断裂且无法被修复时，会产生一种协同致死效应。该现象奠定了合成致死的理论基础，同时被视为一种极具潜力的肿瘤治疗新方向。研究团队基于PARP抑制剂鲁卡帕尼和VHL E3泛素连接酶配体开发靶向降解PARP1的PROTAC 180055。该PROTAC能够在多种细胞高效的降解PARP1，且这种降解是可逆的（图2）。 图2 180055引起PARP1降解 目前临床获批的PARP抑制剂通过与PARP1的NAD结合口袋结合，将PARP1捕获在DNA损伤处。由于该结合口袋在PARP家族保守使得PARP抑制剂常常也能够靶向与PARP家族其他成员，而引起一些临床副作用。为了评估180055对PARP1降解的特异性，研究团队对T47D细胞系进行了基于质谱的定量蛋白质组学分析，结果表明 PROTAC 180055能够专一降解PARP1而无脱靶效应。 图3 180055特异性降解PARP1 此外，在体外实验中，180055能抑制携带BRCA突变的肿瘤细胞，而不影响正常细胞的生长。这表明180055是一种有潜力的PARP1降解分子，值得在临床试验中进一步探索和验证。 图4 180055抑制BRCA突变肿瘤生长 总的来说，研究团队开发了新的靶向降解PARP1的PROTAC降解剂180055，能够高效降解PARP1并抑制其酶活。该分子专一性好，且无DNA捕获效应，能够有效杀伤BRCA突变肿瘤的同时提高安全性。 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://doi.org/10.1038/s41419-024-07277-2 Recently, Gluetacs Therapeutics, in collaboration with the team of Fan Gaofeng from ShanghaiTech University, published an article titled "Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader" in the internationally renowned journal Cell Death & Disease. The article reports on a new generation of PROTAC degraders targeting the PARP1 protein, which inhibit the enzymatic activity of PARP1 while reducing the DNA trapping effect, and demonstrate safe and effective anti-tumor efficacy in BRCA-deficient tumors. Poly (ADP-ribose) polymerase 1 (PARP1), a key enzyme in catalyzing poly (ADP-ribose)ylation reactions within eukaryotic cells, plays a central role in regulating protein post-translational modifications. Specifically, PARP1 is primarily involved in the repair process of single-strand DNA breaks. When PARP1 function is impaired, leading to ineffective repair of single-strand DNA damage, and the homologous recombination repair pathway is hindered due to BRCA gene mutations, this can lead to double-strand DNA breaks that also cannot be repaired, resulting in a synergistic lethal effect. This phenomenon provides a theoretical basis for synthetic lethality strategies, which are considered a highly promising new approach to cancer treatment. The research team developed PROTAC 180055, a PARP1-targeting degrader based on the PARP inhibitor rucaparib and the VHL E3 ubiquitin ligase ligand. This PROTAC can efficiently degrade PARP1 in various cells, and this degradation is reversible. Currently, clinically approved PARP inhibitors bind to the NAD-binding pocket of PARP1, trapping PARP1 at DNA damage sites. Due to the conservation of this binding pocket in the PARP family, PARP inhibitors often also target other members of the PARP family, causing some clinical side effects. To assess the specificity of 180055 for PARP1 degradation, the research team conducted quantitative proteomics analysis based on mass spectrometry in the T47D cell line, and the results showed that PROTAC 180055 could specifically degrade PARP1 without off-target effects. Furthermore, in vitro experiments showed that 180055 could inhibit the growth of tumor cells carrying BRCA mutations without affecting the growth of normal cells. This indicates that 180055 is a potential PARP1 degradation molecule that warrants further exploration and validation in clinical trials. In summary, the research team has developed a new PARP1-targeting PROTAC degrader, 180055, which can efficiently degrade PARP1 and inhibit its enzymatic activity. This molecule has good specificity, no DNA trapping effects, and can effectively kill BRCA-mutated tumors while maintaining high safety. 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 更多信息请浏览www.gluetacs.com 注：转载请注明出处，感谢您对标新生物的关注