This phase Ib trial tests the safety, side effects, and best dose of iberdomide in combination with teclistamab in treating multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Iberdomide is a medication that belongs to a group of drugs known as cereblon E3 ligase modulators. Iberdomide works by targeting and destroying proteins that help myeloma cancer cells to survive. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as teclistamab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving iberdomide in combination with teclistamab may be safe and tolerable in treating patients with relapsed or refractory multiple myeloma.

开始日期2025-07-08

申办/合作机构

National Cancer Institute

NCT05272826 / Recruiting临床2期IIT

A Single Arm, Response-adapted, Open Label Study of Iberdomide, Weekly Bortezomib and Dexamethasone (IberBd) With Isatuximab Added on Demand for Transplant-ineligible, Newly Diagnosed Multiple Myeloma Patients: the BOREALIS Trial

This study will evaluate efficacy and tolerability of iberdomide, bortezomib, dexamethasone and isatuximab on demand administered in combination.

开始日期2025-01-01

申办/合作机构-

NCT06232044 / Not yet recruiting临床1/2期IIT

A Phase I/II Study of the Safety, Tolerability and Efficacy of Belantamab Mafodotin (GSK2857916) in Combination With Iberdomide (CC-220)/Dexamethasone Versus Belantamab Mafodotin (GSK2857916)/Dexamethasone in Relapsed Refractory Multiple Myeloma

This phase I/II trial tests the safety, side effects, best dose, and effectiveness of iberdomide in combination with belantamab mafodotin and dexamethasone in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Multiple myeloma is a cancer that affects white blood cells called plasma cells, which are made in the bone marrow and are part of the immune system. Multiple myeloma cells have a protein on their surface called B-cell maturation antigen (BCMA) that allows the cancer cells to survive and grow. Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Belantamab mafodotin has been designed to attach to the BCMA protein, which may cause the myeloma cell to become damaged and die. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Iberdomide plus belantamab mafodotin may help slow or stop the growth of cancer in patients with multiple myeloma.

开始日期2024-12-31

申办/合作机构

Alliance for Clinical Trials in Oncology

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100 项与伊伯多胺相关的临床结果

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100 项与伊伯多胺相关的转化医学

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100 项与伊伯多胺相关的专利（医药）

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项与伊伯多胺相关的文献（医药）

2024-11-01·Clinical Lymphoma Myeloma & Leukemia

Cereblon E3 Ligase Modulators Mezigdomide and Iberdomide in Multiple Myeloma

Review

作者: van Rhee, Frits ; Patel, Tanvi H ; Al Hadidi, Samer

Multiple Myeloma (MM) remains a challenging hematological malignancy despite significant advancements made during the past 2 decades. Outcomes have improved by incorporating immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies into treatment algorithms that include high dose chemotherapy and autologous hematopoietic stem cell transplantation. However, many patients may eventually relapse despite these innovations. Newer therapies targeting B-Cell Maturation Antigen (BCMA) offer promise for patients with relapsed or refractory disease. BCMA-targeted therapies carry notable side effects, necessitating vigilant monitoring and proactive infection prevention measures. They can also induce considerable immunosuppression, attributed to lower levels of immunoglobulins and increased susceptibility to infections. There is still a need for alternative treatment options with different mechanisms of action that can be easily administered and have a better safety profile. In addition, pomalidomide only overcomes lenalidomide refractoriness in a subset of patients. This review aims to explore 2 next-generation cereblon E3 ligase modulators (CELMoDs), Mezigdomide (CC92480), and Iberdomide (CC-220). We will discuss the biological aspects of these agents, including their mechanisms of action, efficacy, and toxicity profile, and provide a comprehensive review of current literature. Special attention will be paid to ongoing and future clinical trials that provide insights into the potential of these novel therapies in the management of MM.

2024-11-01·Cell Reports Medicine

Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay

Article

作者: Mele, Deanna A. ; Tan, Sin Lih ; Criscione, Steven ; Brucklacher-Waldert, Verena ; Mele, Deanna A ; Bommakanti, Gayathri ; Doshi, Aatman S ; Kurasawa, James ; Buenrostro, Jason Daniel ; Tay, Tristan ; Doshi, Aatman S. ; Gorthi, Aparna ; Karapa Reddy, Iswarya ; Zhang, Ruochi ; Overstreet, Michael Glen ; Prickett, Laura ; Hu, Yan ; Jaensch, Elizabeth

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.

2024-10-01·JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY

Effect of iberdomide on cutaneous manifestations in systemic lupus erythematosus: A randomized phase 2 clinical trial

Article

作者: van Vollenhoven, Ronald ; Dörner, Thomas ; Schafer, Peter H ; Werth, Victoria P ; Korish, Shimon ; Schafer, Peter H. ; Werth, Victoria P. ; Merrill, Joan T. ; Merrill, Joan T ; Furie, Richard ; Li, Stan ; Lipsky, Peter ; Weiswasser, Michael ; Stern, Mark ; Delev, Nikolay

BACKGROUND:

Iberdomide, a cereblon modulator, promotes degradation of transcription factors Ikaros and Aiolos.

OBJECTIVE:

Evaluate iberdomide efficacy and safety in cutaneous lupus erythematosus (CLE) in a phase 2 study.

METHODS:

Patients were randomized (2:2:1:2) to iberdomide 0.45 (n = 81), 0.30 (n = 82), or 0.15 mg (n = 42) or placebo (n = 83) daily while continuing background lupus medications.

RESULTS:

The mean (SD) baseline Cutaneous Lupus Area and Severity Index Activity (CLASI-A) score was 6.9 (7.0); 28% of patients had a score ≥8; 56% had acute CLE, 29% chronic CLE, and 16% subacute CLE. Mean CLASI-A improvement in patients with baseline score ≥8 was 39.7% for iberdomide 0.45 mg versus 20.1% for placebo at week 4 (P = .032), with continued improvement through week 24 (66.7% vs 54.2%; P = .295). Proportions of patients achieving ≥50% CLASI-A reduction from baseline at week 24 were significantly greater for iberdomide 0.45 mg versus placebo for patients with subacute (91.7% vs 52.9%, P = .035) and chronic (62.1% vs 27.8%; P = .029) CLE but not for the overall population (55.6% vs 44.6%) or patients with baseline CLASI-A ≥8 (66.7% vs 50.0%).

LIMITATIONS:

Small patient subgroups of CLE subtypes.

CONCLUSIONS:

Iberdomide showed beneficial effects when added to background lupus medications in patients with subacute and chronic CLE.

项与伊伯多胺相关的新闻（医药）

2024-12-04

·PRNewswire

Stay Ahead in Hematology: Strategic Competitive Intelligence for Informed Decision-Making | DelveInsight

A case study on how a leading pharma company in hematology turned to DelveInsight for long-term competitive intelligence support. DelveInsight provided an in-depth analysis of competitive activity in key hematological malignancies, helping the company stay ahead of the competition. LAS VEGAS, Dec. 4, 2024 /PRNewswire/ -- DelveInsight, a leader in healthcare competitive intelligence and consulting, released a case study on Competitive Intelligence in the Hematology Domain. A Europe-based client approached DelveInsight to evaluate a long-term partnership for insights supporting their clinical, commercial, and launch strategies for a novel oncology product targeting acute myeloid leukemia (AML), multiple myeloma, and acute lymphoblastic leukemia (ALL). The client sought detailed intelligence on competitive activity, class-wise market trends, launch estimates in countries of interest, and regulatory landscapes to inform their development and commercialization plans. An additional request for the segregation of mutation/protein expression-specific therapies was also taken into consideration. DelveInsight provided timely, in-depth analysis of the competitive landscape, emerging therapies, and regulatory situations across multiple countries. This enabled the client to make informed decisions on clinical development, market positioning, and commercialization, helping them stay ahead of the competition in the hematology space. With hundreds of thousands of new cases diagnosed annually, hematologic cancers, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and multiple myeloma, among others present a serious global health challenge while also opening doors for breakthroughs in targeted and personalized treatments. These cancers affect the blood, bone marrow, and lymphatic system, and often require aggressive therapies due to their rapid progression and complex nature. AML and ALL are particularly aggressive, with AML being one of the most common forms of leukemia in adults and ALL affecting both children and adults. Innovations in precision medicine and immunotherapy are transforming hematology, with CAR-T therapies showing promise for leukemias and CELMODs, like Iberdomide, emerging as potential successors to REVLIMID for multiple myeloma. Bristol Myers Squibb's collaboration with Karyopharm on mezigdomide highlights the growing focus on CELMODs. Additionally, FDA-approved therapies like CARVYKTI and TECVAYLI, along with ongoing advancements in bispecific antibodies and proteasome inhibitors, are reshaping the multiple myeloma treatment landscape, despite safety, cost, and manufacturing challenges. The market is rapidly evolving, with new therapies continually entering the pipeline. Several companies, including Bristol Myers Squibb, Celgene, Arcellx, Novartis, Regeneron Pharmaceuticals, Cartesian Therapeutics, Heidelberg Pharma, BeiGene, CARsgen Therapeutics, C4 Therapeutics, AbbVie (TeneoOne), Roche (Genentech), Pfizer, Agios Pharmaceuticals, Jazz Pharmaceuticals, Astellas Pharma, Novartis Oncology, Daiichi Sankyo, AstraZeneca/Astex Pharmaceuticals, Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Autolus Therapeutics, Cellectis, Wugen, Servier, Allogene, and Precision BioSciences, are currently advancing the therapeutic landscape for hematological disorders. As research and innovation progress, there is renewed hope for improving survival rates and enhancing the quality of life for those affected by these challenging diagnoses. DelveInsight's Methodology for Competitive Intelligence in the Hematology Domain helped the client by: Comparative Analyses: Evaluating competitor products to identify strengths, weaknesses, and market positioning, enabling the client to understand where their product stands relative to competitors along with identifying the patient segment with high unmet need KOL Insights: Gathering opinions from Key Opinion Leaders (KOLs) on clinical development strategies, client's product acceptability scenarios, data presentation, probable uptake of their asset,, providing valuable perspectives to refine the client's approach. Current Treatment Paradigms: Analyzing existing treatment approaches to identify market trends, gaps, and unmet needs, helping the client position their product effectively in the market. In-depth Competitive Benchmarking: Assessing competitors' commercial launch preparedness, patient awareness campaigns, and pricing strategies to inform the client's product's market entry and competitive strategy. Market Intelligence: Providing insights into competitors' marketing, sales, and patient engagement approaches, guiding the client's commercialization and go-to-market strategies. Clinical Development Trends: Evaluating clinical trial timelines and strategies, tracking phase shifts in terms of probability of their entry into the higher phase, and analyzing trial data to anticipate future market shifts and inform strategic decision-making. Pricing and Access Strategies: Analyzing competitor pricing models and access strategies, allowing the client to make informed decisions on pricing and reimbursement for their product. Request a proposal to see how DelveInsight's Competitive Intelligence services can support your long-term strategic insights. How DelveInsight's In-Depth Competitive Intelligence in Hematology Helped Clients Stay Ahead in the Market Periodic Competitive Inputs: Provided regular updates on competitor activities, keeping the client informed of market shifts. Enhanced Market Awareness: Delivered ongoing insights into competitor strategies, enabling quick adaptation to market changes. Short-Term Strategies: Developed actionable strategies for immediate response to competitor moves. Counter-Messaging Design: Assisted in crafting counter-messaging strategies to address competitor claims and strengthen brand positioning. Positioning Refinement: Helped refine product positioning to gain a competitive advantage. Promotional Strategy Support: Offered recommendations on promotional tactics to boost market presence and attract key audiences. Why Choose DelveInsight? DelveInsight offers tailored, comprehensive competitive intelligence to keep your hematology product developmental and commercial strategy a step ahead. With expertise in AML, Multiple Myeloma, ALL, and other hematology domains, we support your clinical, commercial, and launch strategies with insights that matter. What Sets Us Apart: Timely Intelligence: Consistent, real-time updates on competitor activities, clinical shifts, and regulatory changes, ensuring you're never caught off-guard. Expert Analysis: From comparative assessments to pricing benchmarks, we provide actionable data that sharpens your positioning. Strategic Edge: We don't just offer data—we deliver strategic recommendations for counter-messaging, promotional tactics, and market adaptation. Choosing DelveInsight means partnering with a team dedicated to turning competitive intelligence into growth and success for your business. Transform your business with our case study. Schedule a call with our DelveInsight Business Development expert today! Conference Coverage Services : DelveInsight's Conference Coverage Services offer a thorough analysis of outcomes from major events like ASH, EHA, AACR, ESMO, ASCO, and others. This detailed examination provides businesses with essential insights for competitive intelligence and market trend forecasting, supporting the formulation of future strategies. Competitive Intelligence Services: DelveInsight's competitive intelligence services provide real-time, accurate insights across the pharmaceutical, life sciences, and medical diagnostics sectors, helping clients stay ahead in a dynamic market. With over 100 years of combined experience, our experts deliver actionable strategic insights, backed by robust research methodologies, to support critical business decisions and create a competitive advantage for our clients. Hematology Pipeline Assessment: Our hematology pipeline evaluation offers a comprehensive overview of cancer treatment options, clinical trials, and key areas within the hematological disorders field, all summarized in an accessible report format. The hematology-focused reports, available in our Report Store, provide in-depth insights into treatment strategies, mechanisms of action (MoAs), drug components, and launch plans for therapies in the late stages of development. This assessment enhances understanding of their launch timelines and strategic initiatives. R&D Analysis: Our skilled research and development analyst specializes in the complexities of hematology, offering essential insights and advice to clients aiming to advance in hematological research and development. They utilize a methodical assessment approach, aligned with industry norms, to track the progress of each hematology drug in both pre-clinical and clinical stages. DelveInsight's comprehensive hematological reports are crafted to reduce uncertainties and highlight overlooked areas, providing organizations with timely and strategic intelligence. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法ASH会议

2024-11-10

·药渡

药渡Cyber解析一种靶向DYRK1A和DYRK1B的强效高选择性PROTAC（DYR684）的发现及功能表征

感谢关注转发，欢迎学术交流回复药渡Cyber，领取文献原文请点击此处链接观看CyberSAR系统详细使用教程快看版小分子诱导的靶向蛋白质降解是新药发现和开发中一种极具前景的方法。神经退行性病变、肿瘤发生、适应性免疫等生理病理过程均与蛋白激酶DYRK1A和DYRK1B密切相关。亚利桑那大学研究团队通过将ATP竞争性DYRK1抑制剂与E3连接酶配体CRBN结合以诱导DYRK1A和DYRK1B的泛素化和降解，首次开发出了一种新型DYRK1蛋白水解靶向嵌合体（PROTAC）。其中，化合物DYR684在细胞水平能够快速、高效、选择性地降解DYRK1A，DYRK1B无酶促活性的剪接变体（p65）则抵抗降解。与竞争性激酶抑制相比，DYR684对DYRK1的靶向降解作用更好地抑制了下游信号，表明DYRKs是PROTAC开发的可行靶点，DYR684有望成为DYRK1A和DYRK1B的特异性化学探针。药渡CyberSAR系统提供了对DYRK1抑制剂分子的深入解析。系统通过聚类结构视图和原始结构视图，展示了与靶点相关的活性分子，并以研发阶段时光轴的形式呈现了潜力Hit。此外，CyberSAR还提供了适应症和试验设计的可视化分析，帮助研发人员快速获取靶向结构信息，开拓研究思路。尽管CyberSAR在本案例分子的初步开发中未被使用，但其在解析和优化药物分子方面显示出巨大的应用潜力。正文版研究背景双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）是一种高度保守的蛋白激酶，在人体组织中广泛表达，是细胞增殖和分化的主要调节因子，与神经退行性改变、肿瘤进展、炎症、糖尿病、心肌梗死、病毒感染等多种疾病密切相关。DYRK1B的催化域与DYRK1A具有85%的序列同源性，但在细胞表达类型上更为有限，被视为潜在的癌症药物靶点。DYRK1A和DYRK1B（统称为DYRK1）在疾病中的过度活跃促使了DYRK1抑制剂的开发，这些抑制剂多为经典的1型激酶抑制剂，通过占据ATP结合位点来干扰酶活性，且难以对DYRK1A和DYRK1B进行区分。分子诱导的靶向蛋白质降解是是新药发现和开发中一种极具前景的方法，PROTAC（蛋白水解靶向嵌合体）作为异双功能分子通过募集E3泛素连接酶来诱导目标蛋白的泛素化和降解。然而，DYRK1A对多种降解剂存在抗性。除DYRK PROTACs外，DYRK1A也可被CaNDY和DYR219通过其他机制降解，但这需要长时间的孵育和较高的药物浓度，这在一定程度上限制了CaNDY和DYR219作为化学探针的使用。本研究通过将ATP竞争性DYRK1抑制剂与E3连接酶配体CRBN结合，首次开发出了DYRK1 PROTAC。其中，化合物DYR684以蛋白酶体依赖性方式诱导了DYRK1A和DYRK1B的有效降解，较传统激酶抑制剂具有更强的DYRK1抑制活性。结果与讨论靶蛋白结合配体的确定 DYR530是在对DYR219进行构效关系研究后开发出的高亲和力DYRK1A抑制剂，较DYR219有更好的选择性和药代动力学性质。研究人员通过解析DYRK1A与DYR530的共晶结构确定了连接子附着位点。DYR530与ATP位点的结合符合I型激酶抑制剂特征。DYR530的2-氨基吡啶和咪唑并吡啶环深入ATP结合口袋并与铰链区中的Lys188、Glu203、Asp307、Leu241形成氢键，2-氨基吡啶与Val306、Phe238形成范德华相互作用，咪唑并吡啶环与Phe238、Leu294、Leu241、Met240、Ala186形成范德华相互作用。N-甲基哌嗪与蛋白质接触较少且朝向溶剂区，是理想的连接子附着位点。 DYRK1 PROTAC的设计与结构优化研究人员将不同长度的PEG连接子连接到DYR530的哌嗪部分，再分别与VHL配体1或CRBN配体泊马度胺相连，得到了DYR617-619、DYR625和DYR622-624。在HEK293细胞中评价这些化合物对DYRK1A和DYRK1B的降解能力，结果表明基于CRBN的PROTAC能显著降低细胞中的DYRK1A水平，而靶向VHL的分子不能有效降解DYRK1A。延长CRBN PROTAC的连接子长度可促进DYRK1的降解，如以4-PEG为连接子的PROTAC（DYR624 - 60% Dmax DYRK1A）的降解作用优于以2-PEG为连接子的PROTAC（DYR622 - 40% Dmax DYRK1A）。接着，研究人员继续对连接子和CRBN配体部分进行了结构优化。将聚乙二醇胺、哌嗪、氮杂环丁烷与沙利度胺的3位偶联，得到了DYR665、DYR696和DYR697；引入CRBN E3连接酶调节剂CC-220（伊伯多胺）得到了DYR662、DYR666、DYR661和DYR660；引入高亲和力CRBN配体5-氨基硫胺100得到了DYR667、DYR684和DYR685。活性评价结果显示，部分化合物的DYRK1A降解能力显著提高，同时它们对DYRK1B也具有一定的降解作用。其中，DYR684的活性最佳，说明吡啶-哌啶可能为活性必须结构。 DYR684的结构特性对DYRK1A/DYR684/CRBN三元复合物结构的模拟结果显示，DYR684跨越了DYRK1A ATP口袋和CRBN沙利度胺结合位点，形成了多重蛋白-蛋白相互作用、盐桥相互作用以及氢键相互作用，这与DYR684的功效和选择性密切相关。对DYR684的激酶组选择性进行分析发现，它命中的激酶数量比DYR530更少。这一结果与先前的研究结论相符，即添加连接子和E3招募配体部分可显著减少与1型激酶抑制剂结合的靶激酶数量。非降解型DYR684类似物的开发通过对戊二酰亚胺上的氮原子进行甲基化得到DYR813。DYRK1降解曲线显示，DYR813在较高浓度下会使DYRK1A水平适度降低，而在较低浓度（100nM）下，DYR813不影响DYRK1A水平，说明DYR684的DYRK1A降解活性与CRBN招募相关。 DYR684浓度依赖性降解DYRK1 用DYR684处理HEK293细胞24小时发现，DYR684以浓度依赖的方式降低了DYRK1A和DYRK1B的水平，对DYRK1A的DC50值为12.3nM，对DYRK1A的最大降解百分比约为90%，对DYRK1B的最大降解百分比约为50%。传统的1型抑制剂DYR530、L41或CaNDY均无法有效降低DYRK1水平。此外，DYR684不改变衔接蛋白DCAF7的水平。DYR684在高浓度下效力的降低可归因于“钩状效应”，这是依赖三元复合物形成的异双功能配体的典型特征。时间依赖性评价用100nM的DYR684处理HEK293细胞，8小时内HEK293细胞中的DYRK1A和DYRK1B几乎达到最大降解程度，随后DYRK1B再次出现，而DYR684对DYRK1A的影响持续了至少48小时，但DYRK1B水平的恢复与基因表达增加无关。最后，研究人员对洗脱后DYR684介导的降解持续时间进行评估发现，洗脱后的48小时内，DYRK1A水平并未恢复，表明DYR684在这些条件下具有持续降解DYRK1A的作用。 DYRK1B剪接变体p65对DYR684诱导的降解具有抗性在图7和图8中，DYRK1B存在代表p69和p65的双条带，残留的DYRK1B信号主要由迁移更快的p65变体引起，进一步的实验证实了p69变体的选择性减少。DYRK1B-p65在激酶结构域内缺少40个氨基酸，是一种无催化活性的假激酶，对PROTAC存在潜在的抗性。通过生成稳定过表达的带有HiBiT标签的DYRK1B-p65的HEK293细胞系进行分析发现，用1μM DYR684处理后，DYRK1A丰度降低较DYRK1B-p69更为显著，而DYRK1B-p65则对降解完全抵抗，这可能是因为PROTAC不能与变化的催化结构域结合。 DYR684通过CRBN介导的泛素化诱导DYRK1蛋白酶体降解研究发现，用过量L41或来那度胺预处理HEK293细胞可阻止内源性DYRK1A/B的降解，说明CRBN结合对于DYR684的降解作用而言是必需的。用NEDD8激活酶（NAE）抑制剂MLN4924进行预处理也减弱了DYRK1A/B的降解，这表明DYR684的降解作用涉及泛素连接酶CRL。用p97解折叠酶抑制剂处理可抑制DYRK1A/B的降解，说明p97解折叠对蛋白激酶的降解至关重要。用蛋白酶体抑制剂硼替佐米进行处理证实了DYRK1A/B的降解取决于蛋白酶体活性。过表达实验验证了泛素与DYRK1A的结合。总之，上述结果表明，DYR684招募E3连接酶配体CRBN以诱导DYRK1A/B泛素化，继而发生p97介导的解折叠和蛋白酶体降解。降解的连续步骤共同影响了PROTAC诱导的靶标降解动力学。为对DYRK1的降解进行实时表征，研究人员对稳定表达GFP-DYRK1A或GFP-DYRK1B融合蛋白的HEK293细胞进行DYR684或非降解类似物DYR813处理，连续6小时监测GFP荧光。结果显示，GFP-DYRK1A被快速有效地降解，初始降解速率约为0.74h⁻¹（t1/2=57min），GFP荧光最大降低98%。GFP-DYRK1B以1.16h⁻¹的速率降解（t1/2=36min），在降解到86%时达到平台期。1μM DYR684对过表达的DYRK1A和DYRK1B的快速降解表明，当内源性DYRK1被100nM的DYR684降解时，蛋白酶体降解所涉及的各个机制步骤都没有饱和，所以这种处理不太可能对细胞蛋白质质量控制系统产生负面影响。癌细胞系中DYRK1A的降解 DYRK1A和DYRK1B是癌症治疗的潜在药物靶点。用DYR684处理不同人类癌细胞系8小时，结果显示DYR684具有细胞系特异性作用，在SH-SY5Y神经母细胞瘤和A549肺腺癌细胞中，DYRK1A发生完全或实质性降解；在PANC-1胰腺癌细胞中，DYRK1A部分降解；HeLa宫颈癌细胞和OVCAR3卵巢癌细胞对DYR684存在抗性。用DYR684处理SH-SY5Y和A549细胞24小时观察到DYRK1A和DYRK1B的持续耗竭。 DYR684对细胞DYRK1活性的影响为评估DYR684对DYRK1A/B下游靶点的影响，研究人员对SF3B1的磷酸化情况进行了评估。10nM的DYR684可近乎最大程度地抑制SF3B1磷酸化，SF3B1磷酸化的降低可能是由于DYRK1的活性被直接抑制或是由于PROTAC诱导的降解作用。通过比较DYR684与非降解对照物DYR813的效果发现，DYR813能部分抑制SF3B1磷酸化，表明其能结合DYRK1并阻断ATP结合位点，同时也说明在100nM浓度下DYRK1未被完全占据，说明对于通过“事件驱动”机制起作用的药物，最大程度的靶点结合并非是高效性的必要条件。 DYR684对蛋白质组的影响为探索DYR684在蛋白质组水平的降解选择性，研究人员进行了无偏倚的定量全局蛋白质组学分析。在HEK293或SH-SY5Y细胞中用100nM的DYR684或溶剂处理24小时后，对6500余种蛋白质进行定量，发现DYRK1A是唯一显著降解的蛋白激酶。在HEK293细胞中未检测到DYRK1B。与Western blot结果一致，DCAF7水平不受DYR684的影响。极少数的蛋白质在处理后表现出显著变化。 DYR684在SH-SY5Y神经母细胞瘤细胞中的细胞毒性作用由于DYRK1A和DYRK1B是癌症治疗的药物靶点，研究人员对DYR684在SH-SY5Y神经母细胞瘤细胞中的作用进行了研究。结果显示，用2μM顺铂、100nM DYR684或两者同时处理细胞会导致中等程度细胞毒性，肉眼观察可发现联合处理的细胞死亡明显增加，表明DYR684降低了神经母细胞瘤细胞的活力，且能与顺铂联合使用。 DYR684的物理化学和药代动力学性质 DYR684在生物相关缓冲液中的溶解度较低，但远高于DC50值。DYR684在肝微粒体和全血中稳定性好。DYR684与蛋白质高度结合，PAMPA数据表明其难以通过血脑屏障。动力学分析显示，DYR684驻留时间长、解离慢。小鼠体内药代动力学参数显示，DYR684腹腔注射后快速吸收，血浆浓度能够在一定时间内维持在DC50值以上，可实现对DYRK1的最大降解。DYR684的高血浆蛋白结合导致其清除率相对较低。目前尚未对DYR684进行体内代谢物鉴定。推测泊马度胺结构可能是导致其血浆不稳定性的因素，将邻苯二甲酰亚胺-戊二酰亚胺换为苯基戊二酰亚胺可增加血浆稳定性。Xenosite软件预测N-脱烷基化和葡萄糖醛酸化可能是DYR684的主要代谢途径。总结本研究基于DYRK1抑制剂DYR530开发出了CRBN招募降解剂DYR684，首次证实了DYRK激酶可被PROTAC降解。DYR684在物理化学和药代动力学特性、效力、靶标选择性、机制验证和非降解对照化合物的可用性方面符合化学探针的关键标准。与传统的1型抑制剂相比，DYR684能持续有效地降低DYRK1A信号，对DYRK1B的不同剪接变体有不同作用。目前，对DYR684的进一步的优化仍在进行，旨在改善药代动力学性质和选择性，以推动DYRK1降解剂的临床转化。文献来源 10.1021/acs.jmedchem.4c01130 请点击此处链接观看CyberSAR系统详细使用教程 1.药渡CyberSAR结合药物设计思想，挖掘了文献及专利报道的活性的结构，通过CyberSAR以方便快速获得研发人员兴趣靶向结构，以供开拓思路，就本文靶点之一DYRK1A举例如下： 2.在靶点界面选中“化学空间”选项标签下级联“聚类结构视图”选项卡，可以将CyberSAR平台收录的文献和专利具有关于靶点相关实验测试活性的分子以“母核结构聚类”的形式展示。其中“绿色字体高亮的”为文献报道的体外酶、细胞活性测试实验中IC50<1000nM的活性分子结构、具体实验、实验结果及实验来源。 3.在靶点界面选中“化学空间”选项标签下级联“原始结构视图”选项卡，可以将CyberSAR平台收录的文献具有关于靶点相关实验测试活性的分子以“研发阶段时光轴”的形式展示。其中绿色高亮展示了潜力Hit。 4.在靶点界面选中“适应症”选项标签，可以可视化直观分析现收集的各类大数据。登录方式 CyberSAR在电脑浏览器端登录网址： https://cyber.pharmacodia.com/，欢迎猛烈试用。请点击此处链接观看CyberSAR系统详细使用教程如需进一步沟通，请扫码添加微信联系药渡赵博士或药渡CyberSAR沟通群。

蛋白降解靶向嵌合体

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2年超130亿美元交易，MNC的下一个必争之地

10月29日，渤健（Biogen）以高达14.5 亿美元的总金额与Neomorph开展研究合作，以发现和开发用于治疗阿尔茨海默病、罕见神经系统疾病和免疫疾病的多个分子胶降解剂。这是进入10月以来的分子胶降解剂领域的第三笔重磅合作，就在渤健宣布与Neomorph合作的前一天，诺华也宣布以超过22亿美元的总价值收购Monte Rosa Therapeutics的一款处于临床阶段的分子胶MRT-6160；此前的10月15日，辉瑞也宣布以总价超15亿美元与TRIANA合作，以发现包括肿瘤学在内的多个疾病领域的多个靶点的新型分子胶降解剂。一个月不到，诺华、渤健、辉瑞等跨国MNC接连携带重金跑步入场，分子胶降解剂领域再次走向风口。 1 分子胶降解剂为何备受巨头青睐？一直以来，传统小分子药物都占据着重要的一席之地，它们就像是一把把精准的钥匙，能够插入疾病相关蛋白的“锁孔”中，阻断其功能，从而达到治疗疾病的目的。但是随着研究的深入，传统小分子药物的局限性也逐渐暴露出来。比如，有些蛋白质缺乏疏水口袋，就像是一把没有锁孔的锁，传统小分子药物这把“钥匙”根本无从插入，难以发挥作用；再者，对于那些起到脚手架作用的蛋白，传统小分子药物也束手无策，无法破坏其功能，存在不可成药性，最后，长期使用传统小分子药物，容易让病菌、癌细胞等产生耐药性。就在传统小分子药物的困境日益凸显的当下，靶向蛋白降解（TPD）技术通过诱导致病靶蛋白的快速降解发挥治疗作用（理论上致病靶点都消失了，不可成药和耐药性的问题自然迎刃而解），成为了小分子药物研发的一种开创性策略。 TPD分为PROTAC（蛋白降解剂）和分子胶降解两大类。PROTAC这几年已逐渐成为新药研发最火热的领域之一，自2013年以来，Arvinas、C4 Therapeutics、Kymera Therapeutics等专注于开发PROTAC技术的企业相继成立，之后，制药巨头默沙东、辉瑞、诺华、勃林格殷格翰、卫材等也纷纷进入该领域。分子胶降解剂是一类可诱导E3泛素连接酶底物受体与靶蛋白之间发生相互作用, 经泛素化被蛋白酶体降解的小分子。但是与PROTAC不同的是，分子胶对E3泛素连接酶和靶蛋白具有双配体结构特征，兼具同两个蛋白结合的功能, 促进两个蛋白发生泛素化, 对那些非可药性靶标以及蛋白-蛋白相互作用也可因之而降解，具有分子量更小，化学机构更简单，空间干扰少和成药性更好的特点。基于技术优势，当前分子胶降解技术正如PROTAC备受追捧。 2 超100亿美元资金注入，分子胶交易频发在医药领域中，MNC的嗅觉无疑是最敏感的，任何一个有利于药物开发的新技术或领域都逃不过MNC的“法眼”。由于分子胶降解技术在一定程度上可克服了不可成药及耐药难题，可到达传统小分子药物无法企及的“角落”，MNC将它视为未来药物开发的革命性突破口。近两年分子胶赛道的交易逐渐火热，据不完全统计，分子胶领域近两年已产生13笔交易，总交易金额超过130亿美元，尤其从2023年下半年开始，交易合作频现，其中今年以来赛道更加火热，已经诞生9笔交易。 2023年以来分子胶领域的交易并购盘点，图源：公开数据整理所有的MNC中，BMS毫无疑问处在领先地位，2019年BMS以740亿美元天价收购Celgene，收获了当时来那度胺（已上市）、CC-92480（Mezigdomide）、CC-99282、CC-220等在研管线，一举稳坐分子胶领域头把交椅。药智数据显示，2005年—2023年，来那度胺累计销售额已达892.1亿美元，于2021年达到销售峰值117亿美元。 2023年，罗氏再次发力分子胶领域，分别于9月、10月与Orionis Biosciences和Monte Rosa Therapeutics两家分子胶明星企业达成超40亿美元合作。可以说，国际上具备创造性开发技术的分子胶公司如Neomorph、Monte Rosa Therapeutics、VantAI、Orionis Biosciences等都颇受MNC及资本的青睐。其中，Neomorph先后与诺和诺德及渤健达成合作；Monte Rosa Therapeutics与罗氏和诺华合作。而最亮眼的Biotech还是AI分子胶发现公司VantAI，当前AI技术的发展也为分子胶的突破带来了机遇，虽然其成立至今无任何融资信息，也无产品管线，却先后获得了勃林格殷格翰、BMS等MNC的重金押注。整体来看，除了罗氏、辉瑞、诺华，其他的MNC如默沙东、礼来、赛诺菲、拜耳、武田、卫材等都在疯狂“围猎”分子胶领域，而且与其他领域引进管线为主不同的是，分子胶领域的交易有很明显的特点是多数MNC以合作开发/引进biotech技术平台为主。值得注意的是，分子胶领域的交易并不只发生在海外，近两年分子胶的热度也传播到了国内，本土biotech的分子胶出海故事正在发生，今年5月，达歌生物牵手武田制药，利用其GlueXplorer平台，针对武田选定的特定疾病靶点发现、验证和优化分子胶降解剂，潜在交易总额最高可达12亿美元；8月，国内分子胶领域交易再传喜讯，嘉越医药以3.45亿美元与美国Erasca就Pan-RAS(ON) 抑制剂JYP0015达成全球独家授权协议。结语越来越多的MNC及Biotech纷纷聚焦分子胶赛道，无疑证明了分子胶具有开启小分子药物研发下一个黄金时代的巨大潜能。截至目前虽然全球已上市、颇具销售规模的分子胶药并不多，仍停留在三大“度胺”：即沙利度胺（Thalidomide）、来那度胺（Lenalidomide）和泊马度胺（Pomalidomide）阶段，但这三款“度胺”强劲的销售表现，也证明了分子胶的市场潜力不容小觑。随着技术的不断进步和临床实践的积累，分子胶领域的神秘面纱正逐渐被揭开，各大MNC的加码，必将加速分子胶药物研发，谁能脱颖而出，拭目以待。参考资料：《160亿元！诺华「跑步」入场》药智网《14.5亿美元！渤健和Neomorph合作开发多个分子胶降解剂》凯莱英药闻本文转载自贝壳社/米朵免责声明本文系转载，仅做分享之用，不代表平台观点。图片、文章、字体等版权均属于原作者所有，如有侵权请告知，我们会及时处理。 ------------------------------ 「长按」二维码添加小达「进群」与更多行业伙伴共探市场前沿资讯艾美达医药咨询艾美达（北京）医药信息咨询有限公司，成立于2014年4月，是一家专业的医药行业咨询服务提供商。公司致力于将产业政策研究与真实世界的数据挖掘深度结合，洞悉行业政策对市场的影响，通过专业的研究提供前瞻性的市场分析，为企业产品上市后的市场准入提供整体解决方案。

蛋白降解靶向嵌合体细胞疗法并购

100 项与伊伯多胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11134	-	-	DB12101

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
多发性骨髓瘤	临床3期	美国	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	日本	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	澳大利亚	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	奥地利	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	比利时	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	巴西	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	加拿大	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	捷克	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	丹麦	Alcami Corp.	2022-06-23
多发性骨髓瘤	临床3期	芬兰	Alcami Corp.	2022-06-23

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04392037 (ICON, ASH2024) 人工标引	临床2期	多发性骨髓瘤	61	IberdomideCyclophosphamideDexamethasone	齋醖願築鏇鬱衊醖製壓(築選簾壓鏇鹹憲願製願) = 願繭網醖壓構積憲積壓遞憲構夢築衊襯觸餘網 (憲壓鹽糧廠製網網積繭, 14 ~ 22) 更多	积极	2024-12-08
ASH2024	N/A	阴燃多发性骨髓瘤	-	Iberdomide	鏇鏇衊構窪鹽積膚壓願(醖繭齋廠鏇簾壓製觸憲) = Six patients were diagnosed with COVID-19 while on study 蓋膚選繭憲顧觸鹹糧襯 (鹽壓鹹網蓋範鏇觸艱餘 ) 更多	-	2024-12-07
				Iberdomide + Dexamethasone
ASH2024	N/A	多发性骨髓瘤	-	Iberdomide	窪範餘願鏇齋構顧獵積(窪蓋鬱鏇醖壓淵願製簾) = 顧獵襯艱蓋夢糧窪鏇顧鹽範積鏇觸襯繭製鑰觸 (衊憲鬱壓餘選廠艱願壓 )	-	2024-12-07
SOHO2024	N/A	-	-	Iberdomide	淵網鬱選簾選艱衊鑰襯(獵願齋築積餘願選範鏇) = Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 70.6% patients; most common were neutropenia (17.6%) and infections (17.6%). Occurrence of other Grade 3–4 TEAEs was low. 醖製顧膚鏇範蓋廠構艱 (繭蓋鏇積餘鏇願願壓襯 )	-	2024-09-04
NCT02773030 (CC-220-MM-001, Pubmed)	临床1/2期	多发性骨髓瘤 CRBN genetic dysregulation	-	Iberdomide	網網製襯簾淵淵網糧醖(鬱淵衊顧鹽艱壓壓鑰範) = 蓋觸構窪齋網襯積衊襯鏇襯廠憲製糧鹽淵糧鹽 (艱網構選選艱餘鹽獵繭 ) 更多	积极	2024-06-18
				Placebo	網網製襯簾淵淵網糧醖(鬱淵衊顧鹽艱壓壓鑰範) = 顧鏇壓繭鑰顧鬱糧選齋鏇襯廠憲製糧鹽淵糧鹽 (艱網構選選艱餘鹽獵繭 ) 更多
NCT04998786 (I2D, ASCO2024)	临床2期	复发性多发性骨髓瘤	70	Iberdomide	夢蓋夢製鏇願糧獵糧遞(範衊齋夢範簾繭憲願蓋) = 獵壓鹹衊選壓糧餘築鹽鏇淵餘壓壓獵壓醖簾製 (襯鑰齋鏇蓋選蓋鏇鹹糧 ) 更多	积极	2024-05-24
				Ixazomib	夢鏇網餘襯鑰鹹壓願壓(積鏇範範鬱淵鑰襯廠襯) = 鹽衊鏇鏇蓋壓製夢選積獵獵壓憲築選鬱膚襯齋 (鬱衊願壓鑰鬱膚積鹹構 )
NCT04392037 (ICON, EHA 12024 \| EHA 22024) 人工标引	临床2期	多发性骨髓瘤	61	IBERDOMIDE+CYCLOPHOSPHAMIDE+DEXAMETHASONE	製壓鬱艱鏇顧夢簾製艱(艱糧鑰觸憲積襯簾積淵) = 蓋蓋選鬱鏇獵齋鏇餘築顧製簾淵積範範蓋鏇顧 (夢鹽構獵積範壓簾窪鹹, 11.9 ~ 22.3) 更多	积极	2024-05-14
				IBERDOMIDE+CYCLOPHOSPHAMIDE+DEXAMETHASONE (patients who had received 2 prior line)	製壓鬱艱鏇顧夢簾製艱(艱糧鑰觸憲積襯簾積淵) = 壓鬱積廠窪鹹獵遞糧範顧製簾淵積範範蓋鏇顧 (夢鹽構獵積範壓簾窪鹹 )
NCT04998786 (I2D, EHA2024) 人工标引	临床2期	多发性骨髓瘤二线	54	Iberdomideixazomibdexamethasone	構鏇餘憲襯範壓憲蓋齋(糧鑰觸壓憲夢鹹鏇壓網) = 製廠艱簾醖淵網遞繭繭淵築積鹽獵衊壓窪積齋 (築構構壓鑰顧鏇鹽遞觸 ) 更多	积极	2024-05-14
NCT02773030 (CC-220-MM-001, EHA2024) 人工标引	临床1/2期	多发性骨髓瘤 CRBN \| Aiolos \| Ikaros	75	Iberdomide 1.0 mgDARATUMUMABdexamethasone	製觸選網願範鹽襯簾鏇(鏇窪製鏇糧襯願網衊簾) = 繭獵鏇遞衊醖廠膚鬱獵構獵網積築鑰艱積製淵 (襯鑰衊鬱遞鏇艱繭觸襯 )	积极	2024-05-14
				Iberdomide 1.3 mgDARATUMUMABdexamethasone	製觸選網願範鹽襯簾鏇(鏇窪製鏇糧襯願網衊簾) = 積淵鹽夢鏇膚壓網夢窪構獵網積築鑰艱積製淵 (襯鑰衊鬱遞鏇艱繭觸襯 )
NCT04564703 (EMN26, EHA 12024 \| EHA 22024) 人工标引	临床2期	多发性骨髓瘤维持	120	Iberdomide 0.75 mg	衊選憲壓淵鬱構窪襯網(齋艱築鹹網願壓衊膚壓) = 醖遞簾選選醖齋衊艱憲製憲餘糧齋齋鑰鑰製憲 (艱糧糧築觸鹹蓋艱製衊, 50 ~ 79) 更多	积极	2024-05-14
				Iberdomide 1.0 mg	衊選憲壓淵鬱構窪襯網(齋艱築鹹網願壓衊膚壓) = 製觸願襯餘顧積鑰齋糧製憲餘糧齋齋鑰鑰製憲 (艱糧糧築觸鹹蓋艱製衊, 19 ~ 48) 更多