CRBN

—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。

-PLX-61639, a selective, oral SMARCA2 degrader, demonstrated sustained PD response and single-agent efficacy in SMARCA4 mutant tumors; program is advancing through IND-enabling studies- -PLX-4545, a selective IKZF2 molecular glue degrader, completely degraded IKZF2 across a range of well-tolerated doses in Phase 1, resulting in a shift from Treg to an effector-like T cell phenotype- -Preclinical data was presented on its CDK2 selective molecular glue degrader, which exhibited superior selectivity over inhibitor-based approaches; program is targeting CCNE1 amplified cancers- SAN DIEGO, April 28, 2025 /PRNewswire/ -- Plexium, Inc. (Plexium), a leading next-generation targeted protein degradation company, announced today multiple presentations with the Company's selective monovalent degrader programs for SMARCA2, IKZF2 and CDK2 at the 2025 American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, IL. "These data highlight the clinical and preclinical progress we've made across our portfolio, including the use of a novel E3 ligase DCAF16, in our SMARCA2 program—an industry first that reinforces the differentiated potential of our monovalent degrader platform," said Jorge F. DiMartino, MD, PhD, Chief Medical Officer at Plexium. "We are also excited to share initial clinical data from PLX-4545, which demonstrated clinical proof of mechanism and intended pharmacological immunophenotypic effects." Oral Presentation Details: Title: "Discovery and characterization of novel, potent and selective CDK2 molecular glue degrader against CCNE1-amplified tumors" Session: MS.ET09.01 – Degraders and Glues Abstract Number: 6375 Date and Time: April 29, 2:55 PM – 3:10 PM Presenting Author: Leenus Martin, PhD Title: "PLX-4545, a selective IKZF2 degrader, reprograms suppressive Tregs leading to tumor growth inhibition and combination benefit with immune checkpoint therapy" Session: MS.ET09.01 – Degraders and Glues Abstract Number: 6380 Date and Time: April 29, 4:10 PM – 4:25 PM Presenting Author: Peggy Thompson, PhD Poster Presentation Highlights: Title: "Mechanistic characterization of selective monovalent direct degraders of SMARCA2″ Session: PO.ET09.04 – Degraders and Glues 1 Abstract Number: 404 Section: 18 Date and Time: April 27, 2025, 2:00 PM – 5:00 PM Presenting Author: Julia Toth, PhD Plexium's SMARCA2 degraders function by bromodomain binding and covalent modification A CRISPR knockout screen identified DCAF16 as being required for PLX-61639 mediated SMARCA2 degradation MOA studies demonstrate PLX-61639-mediated SMARCA2:DCAF16 protein interactions and the requirement of covalent binding to a specific DCAF16 cysteine to support a stable ternary complex and subsequent SMARCA2 degradation Title: "Preclinical characterization of PLX-61639, a potent and orally bioavailable SMARCA2-selective monovalent direct degrader" Session: PO.ET09.10 – Degraders and Glues 2 Abstract Number: 1653 Section: 18 Date and Time: April 28, 2025, 9:00 AM – 12:00 PM Presenting Author: Gregory Parker, PhD Plexium has designed PLX-61639, a potent and selective direct degrader of SMARCA2, and nominated it as a development candidate Daily oral dosing of PLX-61639 results in deep and sustained SMARCA2 degradation, eliciting robust tumor growth inhibition and regression in SM4mut CDX and PDX models, no tumor growth inhibition is observed in a control SM4wt CDX model PLX-61639 is currently advancing through IND-enabling studies Title: "A first in human trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses" Session Title: PO.CT01.02. First-in-Human Phase I Clinical Trials 2 Abstract Number: CT150 Section: 48 Date and Time: April 29, 2025, 9:00 AM – 12 PM Presenting Author: Jorge DiMartino, MD, PhD PLX-4545 an oral, CRBN molecular glue degrader of IKZF2, a lineage-defining transcription factor for Tregs was tested in healthy adult volunteers With repeated daily dosing for 14 days, all dose levels achieved complete degradation of IKZF2 in PBMCs by Day 2 leading to conversion of Tregs into effector-like T cells and an increase in activated T effector cells TEAEs were mostly Grade 1 or 2 (mild or moderate) in severity and no Dose Limiting Toxicities were encountered. All AEs were reversible with discontinuation of dosing The AACR 2025 posters will be made available on the Plexium website. About Plexium Inc. Plexium is the premier, next-generation Targeted Protein Degradation (TPD) company seeking to discover a wide range of monovalent degraders that address the limitations of first-generation heterobifunctional degraders. The company is powered by its proprietary AI-integrated ultra-high-throughput phenotypic drug discovery platform technologies that have enabled the identification of novel small molecules that induce E3 ligase mediated selective degradation of target proteins. From molecular glues to direct degraders, Plexium is advancing a pipeline of novel monovalent targeted protein degraders for the treatment of cancer, neurodegeneration, and other diseases. For more information, visit and engage with us on LinkedIn. Plexium Investor and Media Contact: Amy Conrad Juniper Point [email protected] 858-366-3243 SOURCE Plexium WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

HEFEI, China, April 28, 2025 /PRNewswire/ -- Kangpu Biopharmaceuticals, Ltd. announced today that the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) has approved Phase IIb clinical trial of KPG-818 capsule for the treatment of moderate to severe cutaneous manifestations of systemic lupus erythematosus (SLE). About Cutaneous Manifestations of SLE SLE is a complex, heterogeneous, inflammatory, chronic autoimmune disease in which the body's immune system attacks its own tissues, including skin, joints, and kidneys. Skin is the second most frequently affected organ system of SLE. The majority of SLE patients experience cutaneous manifestations over the course of the disease. Cutaneous manifestations of SLE carries a significant burden with regard to psychosocial well-being and medical costs. Treatment options for cutaneous manifestations of SLE are limited, and current therapies (e.g., glucocorticoids, antimalarials, immunosuppressants) often lack efficacy or carry systemic side effects. There are tremendous unmet medical needs for novel therapeutics, especially an oral agent. About KPG-818 KPG-818 is a novel oral molecular glue modulator of the E3 ubiquitin ligase complex CRL4-CRBN. It demonstrated high binding affinity to CRBN and potent degradation of zinc-finger transcription factors Aiolos (IKZF3) and Ikaros (IKZF1). KPG-818 effectively regulates immune cells (B cells, T cells, and pDC cells) and the release of multiple cytokines, possessing immunomodulatory, anti-angiogenic and anti-tumor effects. In the Phase IIa clinical study in SLE patients completed in the US, KPG-818 was well tolerated and demonstrated promising preliminary efficacy in SLE patients with cutaneous manifestations. KPG-818 was well tolerated in healthy subjects in a Phase I clinical study completed in China. About Kangpu Biopharmaceuticals, Ltd. Kangpu Biopharmaceuticals, Ltd. is a clinical-stage company focused on the discovery and development of innovative therapeutics for the treatment of solid tumors, hematologic malignancies, autoimmune diseases, and inflammatory disorders through novel solutions, including targeted protein degradation. Kangpu has developed a robust pipeline of potential first-in-class and best-in-class drug candidates based on proprietary technology platforms, including NeoMIDES®, gDACs®, and X-SYNERGY®. For more information, please visit . SOURCE Kangpu Biopharmaceuticals WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED