SMARCA4

-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

“点击蓝字 关注我们清华大学生命学院郗乔然研究组联合临床团队揭示了弥漫内生型脑桥胶质瘤潜在的表观遗传治疗靶点 PPS 弥漫内生型脑桥胶质瘤（Diffuse Intrinsic Pontine Glioma，DIPG）是一种高度致命的儿童脑瘤，被称为“儿童杀手”或“死亡恶魔”。该病主要发生于6至7岁儿童脑干的脑桥区域，呈弥漫性生长，属于儿童高级别胶质瘤（pHGG）中最具恶性的一种。由于肿瘤位于“手术禁区”，手术切除几乎不可能。尽管已有超过300项药物治疗的临床试验，但目前仅有放疗可暂时缓解症状，生存期延长有限，五年生存率甚至低于1%。因此，攻克DIPG成为全球神经科学与肿瘤学界的重大难题。2025年4月17日，清华大学生命科学学院郗乔然课题组与首都医科大学附属天坛医院张力伟课题组合作，在《自然·通讯》(Nature Communications) 杂志发表题为 “一种由癌组蛋白驱动的 H3.3K27M/CREB5/ID1 轴维持弥漫内生型脑桥胶质瘤的干性和恶性特征”（An oncohistone-driven H3.3K27M/CREB5/ID1 axis maintains the stemness and malignancy of diffuse intrinsic pontine glioma）的研究论文。该研究系统性阐释了癌组蛋白H3.3K27M通过重塑表观遗传景观激活转录因子CREB5，进而调控ID1表达，从而维持DIPG的干性与恶性，为临床治疗提供了潜在的表观遗传靶点。这项工作是继两个研究团队此前在 Nature Cancer上报道BMP信号通路在不同亚型的DIPG中呈现不同活性后（H3.1K27M亚型BMP信号增强，H3.3K27M亚型BMP信号抑制），进一步深入解析了BMP下游关键靶基因ID1的激活机制。研究表明，尽管在H3.3K27M亚型中BMP信号被抑制，ID1依然高度表达，其表达并非由BMP信号直接驱动，而是由CREB5转录因子通过超级增强子直接激活。这一发现打破了传统“通路—靶基因”线性调控的理解，揭示了癌组蛋白通过CREB5-ID1轴重塑DIPG干性表型的新机制。进一步研究显示，CREB5在正常小鼠脑桥中表达极低，受到HOXA基因簇介导的H3K27me3表观遗传沉默，而在H3.3K27M突变的DIPG细胞中，PRC2功能变化导致H3K27me3水平下降，CREB5因而异常激活。CREB5随后与SWI/SNF复合物核心亚基BRG1协同，激活ID1等下游干性因子，维持肿瘤的干性与增殖能力。体内外实验均表明，敲低CREB5显著抑制DIPG细胞的干性特征与成瘤能力，并延长免疫缺陷小鼠生存期。药物筛选层面，研究团队鉴定出小分子抑制剂ABBV-075可抑制CREB5超级增强子活性，降低CREB5表达、抑制肿瘤生长。联合使用ABBV-075与BRG1抑制剂则产生更显著的协同效果，为表观遗传靶向治疗DIPG提供了新方向。此研究不仅进一步揭示了癌组蛋白在DIPG中重塑转录网络的分子机制，还延续并深化了团队此前关于BMP通路功能差异性的研究成果，为儿童DIPG基础机制研究和临床转化奠定了坚实基础，带来新的治疗希望。清华大学生命学院郗乔然副教授、首都医科大学附属天坛医院张力伟教授为该论文共同通讯作者。清华大学生命学院2019级博士生周威与天坛医院医师徐骋为共同第一作者。生命学院2022级本科生杨双瑞与2019级本科生李浩成参与了实验工作。上海交通大学唐玉杰教授提供了部分DIPG细胞系。生命学院米达副教授团队成员李晓寒和乔慧敏提供了发育小鼠脑片，天坛医院泮长存、蒋壮与谢璐阳提供了临床样本与信息支持。原文链接：https://doi.org/10.1038/s41467-025-58795-2文章来源：清华大学生命学院美编排版：史鑫宇文章审核：周碧远 史鑫宇 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

Preclinical data elucidating the mechanism of action of PRT3789, Prelude’s first-in-class, highly selective SMARCA2 degrader currently in early clinical development Highlights from Prelude’s efforts to discover and develop selective KAT6A degraders, including preclinical data, demonstrating potential for a differentiated efficacy and safety profile WILMINGTON, Del., April 25, 2025 (GLOBE NEWSWIRE) -- Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today announced the presentation of new preclinical data at the American Association for Cancer Research (AACR) Annual Meeting for its highly selective IV SMARCA2 degrader and its highly selective KAT6A degraders. Peggy Scherle, Ph.D., Chief Scientific Officer of Prelude, stated, “We are pleased to provide further preclinical data on the discovery of our lead selective SMARCA2 degrader PRT3789, currently advancing in early clinical development for patients with SMARCA4 mutated cancers. We are also delighted to report initial preclinical data from our selective KAT6A degrader discovery program. These data demonstrate that selectively degrading KAT6A results in robust anti-cancer activity in various pre-clinical models of breast cancer and other solid tumors. We believe that our first-in-class, highly potent KAT6A selective degraders have the potential to expand the therapeutic reach of KAT6A/B inhibitors currently advancing in the clinic, while addressing safety challenges associated with non-selective approaches to this clinically validated target.” Details on the presentations are as follows: Title: Elucidating the Molecular Mechanism of Action of the First-in-Human SMARCA2 Selective Degrader PRT3789 Summary: PRT3789 is a first-in-human SMARCA2 degrader that selectively induces deep and sustained SMARCA2 degradation in preclinical and clinical studies. PRT3789 achieves high selectivity by inducing a more stable ternary complex between SMARCA2 and VHL than SMARCA4 and VHL. K1405 loop in SMARCA2 provides a unique lysine residue to enable selective ubiquitination and also stabilizes the SMARCA2:PRT3789:VHL complex. SMARCA2 resynthesis rate is 2-3 times slower than SMARCA4 thereby enhancing the selectivity profile and contributing to the broad therapeutic index and favorable safety profile observed with PRT3789 in clinical studies to date. PRT3789 is currently under evaluation in Phase 1 and Phase 2 studies in patients with advanced solid tumors with loss of SMARCA4 (NCT05639751 and NCT06682806). Link: Publications – Prelude Therapeutics (preludetx.com) Title: Discovery of First-in-Class Potent and Selective Oral Degraders of KAT6A that Demonstrate Anti-cancer Activity in Pre-clinical Models Summary: KAT6A expression is associated with cancer growth and is recurrently amplified in breast, lung, ovarian and other cancers.¹ KAT6 is a clinically validated target with a dual KAT6A/B inhibitor recently demonstrating promising efficacy in heavily pre-treated patients with ER+/HER2- breast cancer, albeit with potential on-target safety considerations including neutropenia.² Prelude hypothesized that a targeted protein degradation approach could enable discovery of KAT6A selective candidates with potential for improved hematological safety and more robust single agent activity relative to other KAT6-targeted approaches. Prelude believes that it has identified a series of first-in-class, sub-nanomolar, selective and readily orally bioavailable KAT6A degraders now advancing to candidate nomination. Pre-clinical data presented demonstrate that Prelude’s selective KAT6A degraders: Drive significantly deeper anti-cancer responses compared to non-selective KAT6A/B inhibitors across multiple KAT6A-amplified tumors. Disrupt the histone acetyltransferase (HAT) complex resulting in a deeper biological effect on ERα expression. Show sustained activity in ESR1- and Pi3Kalpha-mutated cells, as well as endocrine therapy- and CDK4/6i-resistant cells. Exhibit robust combination benefit with SoC and potential synergy with next generation breast cancer therapies. Deliver robust in vivo target engagement and deep tumor regressions, including complete regressions, in breast and lung cancer xenografts as a monotherapy at low oral daily doses. Display reduced hematologic toxicity compared to KAT6A/B inhibitors. Drive significantly deeper anti-cancer responses compared to non-selective KAT6A/B inhibitors across multiple KAT6A-amplified tumors. Disrupt the histone acetyltransferase (HAT) complex resulting in a deeper biological effect on ERα expression. Show sustained activity in ESR1- and Pi3Kalpha-mutated cells, as well as endocrine therapy- and CDK4/6i-resistant cells. Exhibit robust combination benefit with SoC and potential synergy with next generation breast cancer therapies. Deliver robust in vivo target engagement and deep tumor regressions, including complete regressions, in breast and lung cancer xenografts as a monotherapy at low oral daily doses. Display reduced hematologic toxicity compared to KAT6A/B inhibitors. Link: Publications – Prelude Therapeutics (preludetx.com) About Prelude Therapeutics Prelude Therapeutics is a leading precision oncology company developing innovative medicines in areas of high unmet need for cancer patients. Our pipeline is comprised of several novel drug candidates including first-in-class, highly selective SMARCA2 and KAT6A degraders, and ongoing research into other precision oncology targets. We are also leveraging our expertise in targeted protein degradation to discover, develop and commercialize next generation degrader antibody conjugates (Precision ADCs) with partners. We are on a mission to extend the promise of precision medicine to every cancer patient in need. Our corporate presentation can be found at Events & Presentations – Prelude Therapeutics. For more information, visit preludetx.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates, and the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The words “believes,” “anticipates,” “estimates,” “plans,” “expects,” “intends,” “may,” “could,” “should,” “potential,” “likely,” “projects,” “continue,” “will,” “schedule,” and “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are predictions based on the Company’s current expectations and projections about future events and various assumptions. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, clinical trial sites and our ability to enroll eligible patients, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in Prelude’s Annual Report on Form 10-K for the year ended December 31, 2024, its Quarterly Reports on Form 10-Q and other documents that Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof, except as may be required by law. Investor Contact: Robert A. Doody, Jr. Senior Vice President, Investor Relations Prelude Therapeutics Incorporated 484.639.7235 rdoody@preludetx.com