SMARCA2

CHICAGO — A new type of targeted cancer drug that blocks a “DNA caretaker” protein called Werner helicase has captured the attention of several big pharma companies in recent years, and the first data appear to reinforce its potential. Cells are typically equipped with critical redundancies for important proteins, but when they mutate in cancer patients, a single protein can become the key to a cell’s life or death. By finding the proteins that aberrant cancer cells need to function and then blocking them, drug developers are building the next generation of targeted cancer treatments. Roche now has the first data for its experimental drug, which takes advantage of what’s known as synthetic lethality, in gynecologic and colon cancers. It was shared this week at the American Association for Cancer Research’s annual meeting in Chicago. In the span of six years, scientists and physicians took a promising drug target identified via CRISPR screening and created a handful of experimental treatments for cancer patients. There are now four different Werner helicase-targeting agents in early-stage clinical trials from Roche, Novartis, GSK and Nimbus Therapeutics — a private drug developer with a track record of doing big deals. “Werner helicase really and truly represents a synthetic lethal vulnerability and therefore a therapeutic opportunity in MSI cancers,” said Timothy Yap, a physician-scientist with the University of Texas MD Anderson Cancer Center, referring to cancers with a specific DNA signature. “That’s really the crux of it and why it was so exciting.” Synthetic lethality is a phenomenon that scientists are exploiting to develop new targeted cancer treatments. Their inspiration is PARP inhibitors (such as AstraZeneca’s Lynparza), a class of drugs used to treat a wide range of cancers including breast and ovarian. PARP inhibitors are a synthetic lethal therapy for cancers with BRCA mutations. In the Phase 1 study, Roche’s experimental drug led to four confirmed responses — two in endometrial cancer, one in colorectal cancer, and one in ovarian cancer — in 35 patients. There was also a fifth unconfirmed response in endometrial cancer. Yap presented the data Sunday at the AACR meeting. The responses mean the drug, which came from Roche’s partnership with Vividion Therapeutics in 2020, shrank the tumors in these patients at least 30%. It’s the first time that researchers have shown the effect of a Werner helicase blocker in people. Many of the patients in the study had gone through several previous treatment regimens. While their cancers were found in a wide range of locations, most of the tumors were considered microsatellite instable, which is a sign of DNA misrepair that physicians frequently look for in cancer diagnoses. The initial science that identified Werner helicase as a potential target showed that knocking it out was lethal to the microsatellite instable cells, and this piqued the interest of drug developers. Microsatellite instability-high cancers make up around 3% of all cancer cases, according to some estimates. The responses to Roche’s drug occurred at a range of doses, from 150 mg a day to 1,000 mg twice a day. In an interview, Ryan Corcoran, director of the gastrointestinal cancer center program at the Massachusetts General Hospital Cancer Center, said there’s not a clear correlation between the responses and dose levels. Researchers typically look for dose dependency (more drug equals better efficacy) in clinical studies as a green flag the treatment is working as intended. Corcoran, who chaired the session where Roche’s clinical trial results were presented, consults for Roche but not on the Werner helicase project. The primary side effects related to the drug were nausea, vomiting and diarrhea. There were no dose-limiting toxicities. Like Novartis had already reported, both GSK and Nimbus disclosed at the meeting that their molecules were non-covalent, meaning they do not permanently bind Werner helicase. This leaves Roche as the lone company developing a covalent, or permanently binding, agent in clinical trials. GSK suggested in its presentation that its drug could work in tumors that acquired resistance to Roche or Novartis’ compounds, but that’s based on animal model data and has not been shown in humans. GSK’s drug comes from a partnership with Ideaya Biosciences, a biotech company that’s focused on developing drugs against synthetic lethalities. In 2019, four papers were published showing Werner helicase could be a promising target for treating microsatellite instable cancers. These cancers tend to respond well to immunotherapy, but patients have few other options beyond those treatments. Of the two studies published in Nature on the same day, one was from Mathew Garnett’s lab at the Wellcome Sanger Institute, while the other was led by Adam Bass, who at the time was at the Dana-Farber Cancer Institute and now leads translational cancer research at Novartis. Using CRISPR screening, researchers from both groups found that Werner helicase was needed in microsatellite instable cancer models but dispensable in models that were microsatellite stable. “When you knock out Werner helicase, in 48 hours, the cells are dead,” Garnett said. “All their DNA is just shattered, and it’s really phenomenal. You had this sense when you saw this genome shattering, that there was something really profound happening to these cells.” There are several other synthetic lethality programs in early-stage trials. Corcoran said he has yet to see results from another class of synthetic lethal drugs that matches the success of PARP inhibitors, though many of these efforts are still early and have yet to report clinical data. One closely-watched effort to leverage synthetic lethality is targeting a protein called PRMT5 in cancers with mutations known as MTAP deletions. This is an area in which Bristol Myers Squibb, Amgen, Ideaya and others are all working on early-stage programs, though readouts so far have been mixed . Eli Lilly and Foghorn Therapeutics last year began a Phase 1 trial for a SMARCA2 inhibitor, which they are studying in patients with SMARCA4-mutated cancers. “Imagine you’re riding a bicycle — it’s a bicycle with two wheels — and one of the wheels is lost, and now you’re riding a unicycle,” Foghorn CEO Adrian Gottschalk said. And so giving a SMARCA2 inhibitor to one of these patients is like taking a stick to the cancer cell’s remaining wheel, he said.

买科研服务（代计算、代测试、超算机时），送老李校长“科研理工男士情感课”第一性原理计算解决50年悬而未决难题：半导体中铜为何扩散更快？Ab initio及第一性原理入门参考书介绍《海贼王》告诉你，做科研为什么不能闭门造车……985博导亲测：用DeepSeek写国自然本子，3天完成30天工作量来自公众号：小柯生命本文以传播知识为目的，如有侵权请后台联系我们，我们将在第一时间删除。北京时间2025年4月28日17时，天津医科大学董城联合石磊、陈东星、谢松波团队在《自然—结构与分子生物学》（Nature Structural & Molecular Biology）期刊在线发表了蛋白质靶向降解（TPD）领域的最新研究成果，题为“Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation”。该研究首次将E3连接酶GID4应用于PROTAC分子设计。研究团队设计了基于GID4的PROTAC，实现了多个致病蛋白的靶向降解，并解析了GID4-PROTAC-BRD4三元复合物的晶体结构，系统阐明了GID4介导底物降解的分子机制。这一成果拓展了可用于TPD的E3连接酶工具箱，为未来精准药物研发开辟了新方向。靶向蛋白质降解（TPD）作为一种新兴的癌症治疗策略，受到广泛关注。PROTAC技术以其催化剂量起效、靶向“不可成药”蛋白的独特优势成为TPD领域的代表性技术。然而，目前已应用于PROTAC设计的E3连接酶主要限于CRBN、VHL等少数几种，开发新的E3连接酶成为该领域亟需解决的问题。天津医科大学董城教授课题组长期致力于E3连接酶底物识别机制的基础研究，系统解析了多个重要E3连接酶的底物识别规律，先后报道了E3连接酶GID4、ZYG11B、ZER1、FEM1C、TRIM7、Pirh2、ASB7等分子机制（Nat Chem Biol, 2018；2021；PNAS, 2020；2022；Mol Cell, 2021；Nat Commun, 2022；2023；2024），并在此基础上开发了ZYG11B核酸适配体靶向降解平台（Nat Commun, 2025）。研究人员基于GID4的深窄结合口袋特征，设计了高亲和力小肽PGLW，并联合辉瑞公司进一步开发了GID4特异性小分子配体PFI-7（Nat Chem Biol, 2024）。在本项研究中，作者以PFI-7和BRD4抑制剂JQ1为基础，成功设计出首个GID4-PROTAC先导分子NEP108，实现了BRD4的泛素-蛋白酶体依赖性降解。解析的GID4-NEP108-BRD4三元复合物结构为后续优化提供了重要线索。通过引入刚性哌嗪基团，团队进一步优化出新型降解剂NEP162，不仅增强了三元复合物稳定性，还显著提升了细胞降解效果。晶体结构分析显示，NEP162在三元复合物中存在“J型”与“L型”两种结合构象，揭示了PROTAC介导的三元复合物动态构象特征。a, 基于GID4的NEP162降解剂的化学结构; b, BLI测定GID4-NEP162-BRD4可形成三元复合物; c-d, GID4-NEP162-BRD4不同构象的三元复合物晶体结构在功能验证中，NEP162在细胞水平有效降解BRD4，并表现出抑制细胞增殖、诱导细胞凋亡的生物学活性。在小鼠肿瘤模型中，NEP162（15mg/kg，IP）显著抑制了肿瘤生长，同时显示出良好的体重和器官安全性。进一步研究发现，NEP162能够选择性降解BET家族中的BRD2和BRD4，而对BRD3无明显影响。此外，研究人员还将GID4-PROTAC技术应用于ERα和SMARCA2等其他致病蛋白，验证了其广泛的适用性和潜力。天津医科大学董城教授、石磊教授、陈东星教授和谢松波教授为本研究的共同通讯作者。天津医科大学博士生李艳冉、博士包凯文、博士生孙吉跃及山东师范大学博士葛瑞鑫为共同第一作者。该研究得到国家自然科学基金委、中组部以及免疫微环境与疾病教育部重点实验室、天津医科大学科研共享平台的支持。相关论文信息：https://doi.org/10.1038/s41594-025-01537-1编辑 | 余   荷排版 | 王大雪

—各奖项申报陆续启动，欢迎关注—PROTAC通过招募E3泛素连接酶诱导目标蛋白的泛素化降解，为癌症治疗提供了新策略。然而，目前仅有少数E3连接酶（如CRBN、VHL）被成功应用于PROTAC开发，限制了其靶标范围。4月28日，天津医科大学董城、石磊、陈东星、谢松波团队合作，在Nature Structural & Molecular Biology杂志发表论文，首次将E3连接酶GID4（glucose-induced degradation deficient complex 4，葡萄糖诱导降解缺陷复合物4）应用于PROTAC分子设计。研究团队设计了基于GID4的PROTAC，实现了多个致病蛋白的靶向降解，并解析了GID4-PROTAC-BRD4三元复合物的晶体结构，系统阐明了GID4介导底物降解的分子机制。此外，他们据此开发出高效降解剂NEP162，成功实现BET家族蛋白BRD4的精准清除。研究人员先前已经开发出一种靶向GID4拮抗剂的PFI-7，于是他们假设PFI-7可作为E3连接酶的配体，应用在PROTAC分子中。于是他们将PFI-7与BRD4抑制剂JQ1连接，并通过改变连接链长度，设计了一系列PROTAC分子。通过细胞实验，研究人员发现PROTAC分子NEP108可以降解BRD4，而阴性对照则没有活性。这表明PFI-7可以有效地招募GID4，并促进BRD4的降解。图1. NEP108用于BRD4降解的设计和表征然后，研究人员解析了GID4-NEP108-BRD4三元复合物的晶体结构。其中NEP108分子夹在BRD4和GID4之间，JQ1和PFI-7部分分别与BRD4和GID4的结合位点结合。研究发现，BRD4的BC环和GID4的L3环相互作用，并形成氢键。这与之前报道的VHL基础PROTAC的作用机制有所不同。此外，连接链长度对PROTAC的活性有重要影响，较短的连接链会导致空间位阻，而较长的连接链则可能不利于三元复合物的形成。图2. GID4-NEP108-BRD4三元复合物的晶体结构接下来，研究人员在NEP108的基础上进行结构优化，设计了更有效的PROTAC分子NEP162。后续实验发现，NEP162可以更有效地降解BRD4，并具有更强的GID4结合亲和力。图3. NEP162对BRD4降解的设计和表征通过晶体结构解析，他们发现了GID4-PROTAC-BRD4三元复合物的动态结合模式：NEP162通过连接子将GID4的底物结合腔与BRD4的溴结构域桥接，诱导两者形成可变构象界面，这解释了其增强活性的原因。图4. GID4–NEP162–BRD4三元复合物的结构分析优化后的NEP162在体外展现出纳摩尔级降解效力（DC50=1.2μM），并通过泛素-蛋白酶体系统依赖的方式显著抑制癌细胞增殖。图5. NEP162通过GID4和UPS降解BRD4并抑制细胞增殖在异种移植瘤模型中，NEP162（10mg/kg）治疗显著降低肿瘤内BRD4水平，诱导细胞凋亡，抑制肿瘤生长且无明显毒性。图6. NEP162抑制体内肿瘤生长此外，研究成功将GID4-PROTAC平台扩展至ERα和SMARCA2等其他靶标，证明其广泛适用性。图7. 基于GID4的PROTAC降解其他靶蛋白总结来说，该研究开发了新的E3连接酶GID4，并成功应用于PROTAC设计。该工作不仅丰富了PROTAC可用的E3连接酶库，为“不可成药”靶点提供新工具，同时通过结构驱动的设计策略，为开发高效降解剂奠定了分子基础。参考资料：Yanran Li et al. Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation. Nature Structural & Molecular Biology（2025）https://www.nature.com/articles/s41594-025-01537-1推荐阅读Cell突破：全新VLP递送技术来了2024年，十大制药巨头看上的AI制药公司医药魔方Pro洞察全球生物医药前沿趋势赋能中国源头创新成果转化媒体合作：15895423126Copyright © 2025 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。