GSPT1

“点击蓝字 关注我们科研实力获国际认可！正大天晴2款创新药临床前研究亮相2025 AACR PPS 当地时间4月25日，第116届美国癌症研究协会（AACR）年会在芝加哥开幕。正大天晴2款创新药——四代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）TQB3002、布鲁顿酪氨酸激酶（BTK）靶向降解剂TQB3019的临床前研究被大会收录，意味着研究设计、数据质量和创新性通过了国际同行评审，是对公司科研团队能力的认可。1.研究背景及结论EGFR-TKI已成为EGFR突变阳性晚期非小细胞肺癌（NSCLC）患者的重要靶向治疗手段，但EGFR-TKI耐药是难以避免的临床难题，如由第一代EGFR-TKI耐药产生的T790M突变，以及接受第三代EGFR-TKI治疗后产生的新型C797S耐药突变，耐药问题的出现不断促进新一代EGFR-TKIs的设计与开发。TQB3002是一款全新大环类结构的小分子四代EGFR-TKI。临床前研究[1]显示，TQB3002具有抑制EGFR单突变（如L858R）、双突变（如L858R/T790M）及三突变（如L858R/T790M/C797S）的潜力，对三代EGFR-TKI耐药的C797S突变效果更优。TQB3002在临床前研究中还表现出良好的药代动力学（PK）特性、较低的药物相互作用（DDI）风险和较低的体外心脏毒性，且无明显安全担忧，具有较高的临床开发价值。TQB3002已于2024年相继获得国家药品监督管理局（NMPA）和美国食品药品监督管理局（FDA）的临床试验许可，目前正在中国开展Ⅰ期临床试验。2.关键数据及结果激酶活性和选择性：TQB3002对EGFR单/双突变激酶的IC50（半数抑制浓度）为0.034-0.12nM，优于奥希替尼；对奥希替尼耐药的C797S突变激酶的IC50为0.039-0.093nM，展现出针对耐药突变的强效抑制。抗细胞增殖活性：在EGFR三突变细胞系中，TQB3002具有较强抑制活性，IC50＜0.5nM；在EGFR单/双突变细胞系中，TQB3002的表现优于或相当于奥希替尼。体内抗肿瘤活性：在EGFR单/双/三突变的动物模型中，TQB3002均可剂量依赖性抑制肿瘤生长，且具有良好耐受性；在EGFR三突变PDX（人源肿瘤异种移植）模型中，TQB3002可在剂量≥7.5 mg/kg实现肿瘤退缩；在三突变裸鼠体内单剂量口服10mg/kg后，可抑制肿瘤组织内p-EGFR和p-ERK水平，作用持续至少10小时。 1.研究背景及结论布鲁顿酪氨酸激酶（BTK）的小分子抑制剂在临床上用于治疗多种血液瘤。但是BTK的多种突变，如BTK C481S、BTK L528W会导致已上市的共价和非共价抑制剂出现耐药。BTK蛋白降解剂作为新一代BTK靶向疗法，有望解决BTK上市药物的耐药问题。TQB3019是基于正大天晴蛋白降解剂技术平台（OAPD®）开发的一种强效、高选择性的口服BTK降解剂。临床前研究[2]显示，TQB3019对多种耐药突变（包括共价抑制剂的耐药突变C481X及非共价抑制剂的耐药突变T474I、L528W等）展现出广谱抑制活性，具有解决BTK抑制剂获得性耐药问题的潜力。TQB3019已于2025年4月获得中国IND批准，即将进入I期临床试验阶段。2.关键数据及结果降解活性：TQB3019在弥漫大B细胞淋巴瘤细胞系OCI-LY10和TMD-8中以时间和剂量依赖性诱导BTK蛋白降解，与处于临床研究的BTK降解剂NX-5948的降解活性相当，优于NX-2127。激酶抑制活性与选择性：TQB3019优于其它BTK靶向抑制剂和降解剂。对BTK耐药突变细胞系的增殖抑制活性：在携带野生型BTK和临床耐药相关突变（C481S/F、T474I、L528W、V416L）的各细胞系，TQB3019均有较强的细胞增殖抑制活性，优于其它的小分子抑制剂和蛋白质降解剂，具有克服已上市的共价/非共价抑制剂由于BTK突变导致获得性耐药的潜力。体内抗肿瘤活性：在BTK野生型TMD-8异种移植瘤模型中，TQB3019可剂量依赖性抑制肿瘤生长，30mg/kg剂量下出现肿瘤消退。各剂量组小鼠耐受良好未出现体重显著下降。成药性和体外安全性：TQB3019具有良好的口服生物利用度和体外安全性。蛋白质降解选择性：TQB3019对BTK具有高度的降解选择性，对具有潜在安全性风险的CRBN底物（GSPT1、IKZF1/3）均无明显降解作用。参考文献 ：[1] Xun Chen, Lihua He, Xin Tian, Fei Liu, Hongjiang Xu, Ling Yang, Wei Zhao, Xiquan Zhanget al. TQB3002:a potent fourth-generation small molecule EGFR-TKI.2025 AACR.[2] Jing Ren, Jinan Wang, Sheng Xu, Jin Liu, Ying Zhang, Xiaojin Wang, Baomin Liu, Wei Shi, Hongjiang Xu, Ling Yang, Wei Zhao, Xiquan Zhang,et al. Preclinical Development of TQB3019: A Potent and Selective Oral BTK Degrader Leveraging the OAPD® Platform to Overcome Acquired Resistance Mutations.2025 AACR.文章来源：正大天晴美编排版：覃冰冰文章审核：杜雪丽 覃冰冰 罗琪【免责声明】以上内容来源于互联网，不代表本平台立场或观点；如有侵犯作者著作权，请及时与我们联系（Tel：025-83271227，或直接在微信平台留言），我们将及时更正或删除。《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。《药学进展》编委会由国家重大专项化学药总师陈凯先院士担任主编，编委由新药研发技术链政府监管部门、高校科研院所、制药企业、临床医院、CRO、金融资本及知识产权相关机构近两百位极具影响力的专家组成。联系《药学进展》↓↓↓编辑部官网：pps.cpu.edu.cn；邮箱：yxjz@163.com；电话：025-83271227。欢迎投稿、订阅！往期推荐聚焦“兴药为民·2023生物医药创新融合发展大会”“兴药为民·2023生物医药创新融合发展大会”盛大启幕！院士专家齐聚杭城，绘就生物医药前沿赛道新蓝图“兴药强刊”青年学者论坛暨《药学进展》第二届青年编委会议成功召开“兴药为民·2023生物医药创新融合发展大会”路演专场圆满收官！校企合作新旅程已启航我知道你在看哟

BOSTON, USA & DAEJEON, South Korea, April 28, 2025 – Orum Therapeutics, Inc. (“Orum” or the “Company”) (KRX: 475830), a public biotechnology company pioneering the field of degrader-antibody conjugates (DACs), today announced a strategic update to its pipeline. Orum has discontinued further clinical development of ORM-5029, a HER2-targeted GSPT1 degrader-antibody conjugate (DAC). This decision follows an internal assessment of the program’s clinical progress and incorporates information previously disclosed. Concurrently, Orum announced the nomination of a new drug candidate, ORM-1153, in development for the treatment of hematologic malignancies. ORM-1153 is a novel DAC engineered using Orum’s proprietary Dual-Precision Targeted Protein Degradation (TPD²®) approach, which combines the catalytic protein degradation mechanism of TPDs with the tumor-targeting capabilities of therapeutic antibodies. The candidate targets GSPT1, a translation termination factor highly relevant in hematologic malignancies, and an undisclosed tumor-associated antigen to enhance selectivity and broaden the therapeutic window. In preclinical studies, ORM-1153 demonstrated potent anti-tumor activity and a favorable safety profile, including in non-human primate models. ORM-1153 demonstrated picomolar potency in target-expressing cell lines and showed greater potency than existing small molecule GSPT1 degraders. In vivo, a single dose of ORM-1153 led to strong anti-tumor activity in relevant xenograft models. Orum plans to advance the program into IND-enabling studies and anticipates presenting additional data at a scientific conference later this year. “After careful review of available clinical and preclinical data, we have concluded clinical development of ORM-5029,” said Sung Joo (SJ) Lee, Ph.D., Founder and CEO of Orum Therapeutics. “This decision reflects our continued commitment to patient safety and our strategic focus on advancing the next generation of degrader-antibody conjugates with a clearly defined risk-benefit profile. We look forward to advancing next-generation programs emerging from our proprietary platform, like ORM-1153.” Dr. Lee continued, “ORM-1153 leverages learnings from all our programs and clinical experience to build potent, selective, and tumor-targeted protein degrader therapeutics that address serious unmet needs in oncology. We remain confident in the promise of our Dual-Precision Targeted Protein Degradation GSPT1 platform and are excited to progress this new candidate toward the clinic.” About Orum’s TPD²® Approach Orum’s unique Dual-Precision Targeted Protein Degradation (TPD²®) approach builds novel targeted protein degraders combined with the precise cell delivery mechanisms of antibodies to generate innovative, first-in-class, cell-selective TPDs for the treatment of cancer. Orum has developed new targeted protein degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, the payloads are designed to be delivered specifically to target cells and precisely degrade the intracellular target protein of interest. About Orum Therapeutics Orum Therapeutics is a public biotech company pioneering the development of cell-specific, targeted protein degraders (TPD²®) with the precision of antibody targeting to improve cancer treatment for more patients. The company is advancing its GSPT1-directed TPD² programs and developing novel degrader payloads to expand the potential of targeted protein degradation. Orum's novel targeted protein degrader payloads are designed to selectively degrade key intracellular proteins, offering a highly targeted approach to treating difficult-to-treat diseases. Orum is located in Daejeon, South Korea, and Lexington, MA, US. For more info, visit www.orumrx.com. Orum Therapeutics Forward-Looking Statements This press release contains forward-looking statements that are based on the current expectations and beliefs of Orum Therapeutics, Inc. (“Orum”). Statements in this release regarding matters that are not historical facts, including, but not limited to, statements relating to the potential selectivity, therapeutic window, therapeutic benefits, and indications for ORM-1153; the potential for preclinical study results to indicate positive results in IND-enabling studies and any clinic trial; the potential for commencement of IND-enabling studies, the filing and approval of any IND application, and initiation of clinical trials; the presentation of additional ORM-1153 data during 2025; the promise of Orum’s GSPT1 platform; and the development of new payload platforms and programs and the expansion of Orum’s pipeline are forward-looking statements. These forward-looking statements are based on management’s expectations and assumptions as of the date of this release and are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, the uncertainty of success in research and development activities; the uncertainty in approval of any IND that might be filed; competition from alternative therapies; and risks related to the recruitment and retention of key employees, fluctuating markets and economic conditions, and future fundraising. The forward-looking statements in this presentation speak only as of the date of this release, and Orum undertakes no obligation to update or revise any of the statements. Orum cautions investors not to place considerable reliance on the forward-looking statements contained in this release. Contacts Corporate: Kayla (Gyebang) Mo, Director, IR/PR, Orum Therapeutics, Inc., media@orumrx.com Media: Jessica Yingling, Ph.D., President, Little Dog Communications Inc., jessica@litldog.com

1. 研究背景分子胶降解剂（Molecular glue degraders, MGs）通过重构E3泛素连接酶与靶蛋白的相互作用界面，诱导形成三元复合物以启动蛋白酶体降解通路，为靶向传统不可成药靶点提供了创新范式。然而，现有研究手段存在显著局限性：化学蛋白质组学与亲和富集质谱技术主要聚焦于终末降解事件，难以动态捕获E3连接酶与底物间的瞬时弱相互作用，导致非降解性新底物（neo-substrates）的系统性漏检，这不仅制约了靶点空间的拓展，更影响对分子胶作用机制的深度解析。尤为突出的是，处于临床研究阶段的分子胶（如DKY709）其底物谱系尚未完全解析，且缺乏高通量解析其诱导的E3连接酶互作组的有效工具，这些瓶颈严重阻碍了新一代降解剂的理性设计。2. 研究目的针对上述科学难题，陈小华/谭敏佳团队在《Angew. Chem. Int. Ed.》发表题为《Crosslinking Profiling of Molecular Glue Degrader-Induced E3 Ligase Interactome to Expand Target Space》的研究，开发了基于基因编码光交联非天然氨基酸（UAA）与质谱蛋白质组学联用的全局交联分析策略。本研究构建了三个递进式研究体系：(1) 通过CRBN底物结合域特定位点的UAA整合，实现在活细胞水平精准捕获分子胶（CC-885、DKY709）诱导的CRBN-底物瞬时互作；(2) 系统性鉴定CRBN降解依赖性与非依赖性新底物（FIZ1、ZFP91等），揭示其底物识别基序并并扩展其靶点空间；(3) 基于结构机制设计新型分子胶降解剂CM-2/CM-3，通过TR-FRET和细胞毒性实验验证其通过重塑CRBN互作网络增强抗肿瘤效能的可行性。该技术为分子胶的机制研究及临床转化提供了高效工具，并为克服“不可成药”靶点难题开辟新路径。 3. 研究结果成果一：CRBN互作网络解析通过UAA介导的光交联捕获技术，揭示了CC-885诱导的CRBN动态互作网络。Western blot与质谱联用技术验证了CRBN-GSPT1复合物的特异性形成，阐明CC-885通过精确调控CRBN构象改变实现GSPT1选择性降解的分子基础，为分子胶的靶向性机制提供了直接实验证据。成果二：DKY709底物谱系拓展结合分子对接与定量质谱分析，不仅验证了DKY709的已知降解靶标，更发现FIZ1作为新型CRBN依赖性降解底物。进一步的蛋白丰度测定和Western blot结果证实，FIZ1降解受DKY709诱导，并依赖CRBN介导的泛素-蛋白酶体途径。该研究拓展了CRBN介导的底物谱，同时也为优化临床候选药物的脱靶效应评估提供了关键数据。成果三：理性药物设计突破基于lenalidomide的构效关系优化，成功设计出CM-2、CM-3系列衍生物。分子对接模拟表明，CM-2和CM-3在CRBN结合口袋中具有更优的配体构象，并通过 TR-FRET实验验证了其较高的CRBN亲和力。此外，在MM.1S细胞中，这些新型降解剂表现出更强的细胞毒性和降解活性，表明其在血液瘤治疗中的潜在应用值。    成果四：降解动力学机制阐明分析了分子胶降解剂CM-2和CM-3诱导的靶蛋白降解机制。Western blot结果表明，ZFP91和FIZ1在CM-2处理后显著降解，而蛋白酶体和NEDD8途径抑制实验进一步确认，该降解依赖于CRBN介导的泛素化过程。此外，时间梯度实验揭示了CM-3诱导GSPT1和CK1α降解的动力学模式，为MG降解剂的作用机理提供了更深入的证据。4. 研究结论本研究创新性地构建了光交联蛋白质组学技术平台，实现了分子胶诱导的E3连接酶互作网络解析，并拓展了其潜在靶点范围，为新型降解剂的设计提供了关键结构信息。基于结构机制设计的CM-2、CM-3系列衍生物，在临床前模型中展现出显著优化的药效学特征。该技术平台不仅为分子胶作用机制研究提供了有力工具，更为突破"不可成药"靶点治疗瓶颈开辟了新途径。研究建立的"靶点发现-机制解析-药物设计"三位一体研究范式，为靶向蛋白降解领域的发展提供了方法论创新。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓