预约演示

更新于：2025-07-24

Duvelisib hydrate

度维利塞

更新于：2025-07-24

概要

基本信息

药物类型

小分子化药

别名

Duvelisib、度恩西布、杜韦利西布

+ [6]

靶点

PI3Kγ x PI3Kδ

作用方式

抑制剂

作用机制

PI3Kγ抑制剂(磷脂酰肌醇-3激酶γ抑制剂)、PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [2]

在研适应症

慢性淋巴细胞白血病滤泡性淋巴瘤小淋巴细胞淋巴瘤+ [35]

非在研适应症

侵袭性非霍奇金淋巴瘤哮喘CD20阳性滤泡性淋巴瘤+ [10]

原研机构

Infinity AS

在研机构

Secura Bio, Inc.

Memorial Sloan Kettering Cancer Center

石药集团中奇制药技术（石家庄）有限公司

非在研机构

Infinity Pharmaceuticals, Inc.

AbbVie, Inc.

石药集团欧意药业有限公司

+ [2]

权益机构

Yakult Honsha Co., Ltd.

Verastem, Inc.

Mundipharma International Ltd.

+ [12]

最高研发阶段批准上市

首次获批日期

美国 (2018-09-24),

慢性淋巴细胞白血病滤泡性淋巴瘤小淋巴细胞淋巴瘤

最高研发阶段(中国)批准上市

特殊审评快速通道 (美国)、加速批准 (美国)、孤儿药 (美国)、孤儿药 (欧盟)、附条件批准 (中国)、优先审评 (中国)

登录后查看时间轴

结构/序列

分子式C22H17ClN6O

InChIKeySJVQHLPISAIATJ-ZDUSSCGKSA-N

CAS号1201438-56-3

关联

项与度维利塞相关的临床试验

NCT07001384

/ Not yet recruiting临床1期IIT

A Phase I Study of Alectinib Plus Duvelisib in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma (ALK+ ALCL)

The researchers are doing this study to see if alectinib in combination with duvelisib is a safe and effective time-limited treatment for people with relapsed or refractory ALK+ anaplastic large cell lymphoma (ALCL). The researchers will test different doses of the study drugs to find the highest doses that cause few or mild side effects in participants. Once they find this dose combination, they will test it in a new group of participants to learn how long the effect of the combination lasts after the end of treatment

开始日期2025-07-01

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+2]

NCT06522737

/ Recruiting临床3期

A Multicentre, Open-label, Phase 3, Randomised Controlled Trial of Duvelisib Versus Investigator's Choice of Gemcitabine or Bendamustine in Patients With Relapsed/Refractory Nodal T Cell Lymphoma With T Follicular Helper (TFH) Phenotype

The study will evaluate the progression-free survival benefit of duvelisib monotherapy as compared to investigator's choice of gemcitabine or bendamustine in participants with relapsed/refractory nodal T cell lymphoma with TFH phenotype.

开始日期2025-05-19

申办/合作机构

Secura Bio, Inc.

NCT06810778

/ Recruiting临床1/2期IIT

Phase I/II Study of Duvelisib and Venetoclax in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)

This is an open-label, phase I/II study of duvelisib in combination with Venetoclax for patients with relapsed/refractory NHL. Duvelisib is an FDA approved, marketed product used to treat certain patients with leukemia and lymphoma and Venetoclax, which is approved for treatment of certain patients with acute myeloid leukemia. The combination of these two drugs is experimental. Experimental means that it is not approved by the United States Food and Drug Administration (FDA). The researchers want to find out how safe it is to combine these drugs and how well this combination can work for your cancer.

开始日期2025-05-02

申办/合作机构

Jonsson Comprehensive Cancer Center

100 项与度维利塞相关的临床结果

登录后查看更多信息

100 项与度维利塞相关的转化医学

登录后查看更多信息

100 项与度维利塞相关的专利（医药）

登录后查看更多信息

332

项与度维利塞相关的文献（医药）

2025-10-01·COMPUTATIONAL BIOLOGY AND CHEMISTRY

Identification of Therapeutic Compounds Targeting Phosphatidylinositol 3-Kinase (PI3K) Through Molecular Docking, Dynamics Simulation, and DFT Calculations

Article

作者: Zaki, Magdi E A ; Al-Dies, Al-Anood M ; Bayıl, Imren ; Silva, Gabriel Vinícius Rolim ; Oliveira, Jonas Ivan Nobre ; Alqahtani, Taha ; Tayyeb, Jehad Zuhair ; Guendouzi, Abdelkrim ; Alves, Guilherme Bastos

Cancer is one of the leading causes of death worldwide and characterized by uncontrolled cell proliferation. The phosphatidylinositol 3-kinase (PI3K) is an enzyme, which is essential for regulating cell growth and survival, is often dysregulated in tumors. Currently available PI3K inhibitors (like Duvelisib) have significant side effects, highlighting the need for safer therapeutics. Gallic acid, a natural phenolic compound with remarkable antineoplastic properties, showcases a promising scaffold for drug development. The aim of this study is to identify potential PI3K inhibitors from gallic acid derivatives using advanced computational techniques such as PASS prediction, molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. Five derivatives 21, 37, 44, 68 and 75 were selected based on their predicted antineoplastic activity among 90 derivatives, as well as the control drug Duvelisib. Compound 68 proved to be the most promising candidate, exhibiting strong binding affinity to the PI3K receptor, forming multiple hydrogen bonds with key residues, and showing stable interactions over 500 ns MD simulation. ADMET analysis revealed that compound 68 had favorable pharmacokinetic properties. Compound 21 also showed strong binding affinity but exhibited limitations in its pharmacokinetic profile. This study aims to improve our understanding of ligand-protein dynamics in PI3K inhibition and highlight the potential of gallic acid derivatives in developing safer and more effective PI3K inhibitors for cancer therapy. Our results support further experimental validation of compound 68 and suggest that gallic acid derivatives could contribute to the development of safer therapies.

2025-06-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes

Review

作者: Hossain, Md Arafat ; Hossain, Md Takdir

The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.

2025-06-01·JOURNAL OF THE INDIAN CHEMICAL SOCIETY

A shorter and alternative route to duvelisib: Application in scale-up synthesis

作者: Pal, Manojit ; Suresh, Garbapu ; Venkateshwarlu, Rapolu ; Buddepu, Srinivasa Rao ; Moturu, Kishna Murthy V. R. ; Siddaiah, Vidavalur

A short, convenient and alternative synthesis of the oncol. drug duvelisib is reported along with the development of chem. and chiral (wherever applicable) HPLC methods for product obtained in each step.The key features of the newly developed process include: (i) direct conversion of the intermediate possessing a Boc protected amino group to a new intermediate where the Boc group was replaced by the 7H-purin-6-yl moiety (via a two-step method involving the amine deprotection followed by reaction with 6-chloropurine), (ii) direct use of 6-chloropurine without employing any N-protection/deprotection strategy, and (iii) the construction of the isoquinolinone ring using a densely substituted intermediate at the end stage.The optimization of the two newly adopted steps was carried out in the 10 g scale and the feasibility of the optimized conditions (involving the use of ZnCl₂ in both cases) in the scale-up preparation was verified by conducting the reaction in 100 g scale.The current alternative synthesis that involve nearly 3 fewer steps than the previous method afforded the desired product duvelisib in 38% overall yield (better than 19% overall yield of the reported method) that was purified further via the formation of a salt of (1R)-(-)-10-camphorsulfonic acid followed by converting back to the free base. 2009 Elsevier Ltd.All rights reserved.

132

项与度维利塞相关的新闻（医药）

2025-07-07

·生物谷

Blood Adv：突破性疗法！双药联合为复发难治性T细胞淋巴瘤患者带来新希望

来自麻省总医院癌症研究中心等机构的科学家们通过研究首次在真实世界中评估了杜韦利西布联合罗米地辛（duv/romi）对R/R的PTCL/CTCL患者的疗效和安全性，从而为临床实践提供了重要的依据。近年来，淋巴瘤的发病率在全球范围内呈上升趋势，其中T细胞淋巴瘤（PTCL/CTCL，外周T细胞淋巴瘤/皮肤T细胞淋巴瘤）因侵袭性强、预后差，常常成为临床治疗的难点。据统计，外周T细胞淋巴瘤（PTCL,peripheral T-cell lymphomas）占非霍奇金淋巴瘤的10%-15%，而复发或难治性（R/R）患者的5年生存率不足30%，远低于B细胞淋巴瘤。传统化疗方案对这类患者效果有限，且易伴随严重副作用，因此科学家们急需开发更安全有效的靶向疗法。如今，PI3K抑制剂（比如杜韦利西布）和组蛋白去乙酰化酶抑制剂（比如罗米地辛）的联合应用成为研究热点，这一组合能通过双重调控肿瘤细胞的增殖和凋亡通路，从而展现出协同抗肿瘤潜力。美国血液学会（ASH）2024年年会上公布的初步数据显示，该方案在早期临床试验中疗效显著，但真实世界中的表现仍需验证。近日，一篇发表在国际杂志Blood Advances上题为“Real-world Evidence of Duvelisib and Romidepsin in Relapsed/Refractory Peripheral and Cutaneous T-cell Lymphomas”的研究报告中，来自麻省总医院癌症研究中心等机构的科学家们通过研究首次在真实世界中评估了杜韦利西布联合罗米地辛（duv/romi）对R/R的PTCL/CTCL患者的疗效和安全性，从而为临床实践提供了重要的依据。这项研究中，研究人员旨在填补临床试验与真实世界应用之间的证据缺口；与严格控制的临床试验不同，真实世界研究纳入了更广泛的患者群体，包括高龄、多线治疗失败及伴有合并症的患者，结果更具普适性。研究人员采用回顾性与前瞻性结合的观察性设计，纳入了2016年至2024年间接受duv/romi治疗的38例R/R PTCL/CTCL患者，覆盖多种亚型（如nTFH、PTCL-NOS、CTCL等），参与者中位年龄62岁，61%为原发难治性患者。研究人员让患者接受杜韦利西布（口服）联合罗米地辛（静脉注射）治疗，剂量参考前期临床试验的推荐方案。疗效评估采用国际恶性淋巴瘤影像工作组标准，通过PET/CT和Deauville评分系统判定。安全性数据通过电子病历持续采集，不良事件（AE）按CTCAE 5.0标准分级，研究重点观察患者总体缓解率（ORR）、完全缓解率（CRR）、无进展生存期（PFS）及治疗相关毒性。现实世界中接受Duv/Romi联合治疗的R/R PTCL和CTCL患者的无事件生存率研究结果表明，这种联合疗法所产生的疗效显著，患者的总体缓解率达61%，完全缓解率为47%，其中nTFH亚型患者获益更明显（ORR 82% vs. 非nTFH 43%）；同时患者的生存状况得到了改善，nTFH患者的中位无进展生存期为11个月（非nTFH仅3.3个月），11例患者成功桥接至异基因造血干细胞移植（allo-HSCT），移植后存活率100%；此外，这种联合性疗法的安全性可控，患者常见3-4级不良事件为血液学毒性（如中性粒细胞减少42%），但仅4例因不良事件停药，1例死亡（脓毒症）。综上，本文研究结果表明，duv/romi方案在真实世界中仍保持高效低毒的特点，尤其为nTFH亚型患者提供了显著的生存获益，且桥接至异基因造血干细胞移植的成功率为后续治愈奠定基础；与同类联合方案（如罗米地辛+阿扎胞苷）相比，患者的完全缓解率更高（47% vs. 38%），且未增加移植后并发症风险。然而，本文研究也存在一定的局限性，包括样本量较小，且部分数据依赖回顾性记录。后期研究人员还将进一步深入研究，通过Ⅲ期随机试验进一步验证，并探索分子标志物从而精准筛选获益人群。综上，duv/romi为R/R PTCL/CTCL提供了一种极具前景的治疗选择，尤其适合移植候选患者，其“快速起效+低毒性”的优势或可改写临床指南。（生物谷Bioon.com）参考文献： Josie G Ford,Min Jung Koh,Alexandra W Lenart，et al. Real-world Evidence of Duvelisib and Romidepsin in Relapsed/Refractory Peripheral and Cutaneous T-cell Lymphomas, Blood Advances (2025). DOI:10.1182/bloodadvances.2025016347

突破性疗法临床结果

2025-06-09

·EINPresswire

Secura Bio Announces First Patient Dosed in Phase 3 TERZO Study of COPIKTRA® (duvelisib) in Relapsed/Refractory Nodal T-follicular Helper Cell Lymphoma

Interim data from the first phase 3 study of a PI3K inhibitor to treat relapsed or refractory nodal T-follicular helper cell lymphoma (nTFHL) anticipated in early-2027 SUMMERLIN, Nev., June 09, 2025 (GLOBE NEWSWIRE) -- Secura Bio, Inc. ( www.securabio.com ), an integrated pharmaceutical company maximizing commercial outcomes for oncology medicines, today announced that the first patient has been dosed in its Phase 3 TERZO study of COPIKTRA (duvelisib) in adults with relapsed or refractory (R/R) nodal T-follicular helper cell lymphoma (nTFHL), a disease where there are currently no well-established standards of care for patients with relapsed or refractory disease. “Patients with relapsed or refractory nodal T-follicular helper cell lymphoma need meaningful treatment options, with the potential to extend and improve the quality of their lives,” said Dr. Graham Collins, UK Site Investigator for the Terzo Study. “I am grateful to Secura Bio for continuing to evaluate COPIKTRA for diseases where the standard treatment protocol has been challenged by recurring relapses and mutations.” The Phase 3 TERZO study is a multicenter, open-label, randomized controlled study of duvelisib versus investigator’s choice of gemcitabine or bendamustine in patients with R/R nTFHL. Patients in the European Union (CT: 2024-516605-23-00) and the United Kingdom (NCT06522737) will be randomized on a 1:1 basis and receive treatment until progressive disease (PD) or unacceptable toxicity. The primary endpoint of the study is progression-free survival. Secondary endpoints include overall survival, objective response rate, complete response rate, duration of response, number of participants with adverse events, and quality of life. The company expects to enroll approximately 124 patients with interim data from the study anticipated in early-2027. “We are very pleased to have dosed our first patient in this Phase 3 study of COPIKTRA based on the results from our Phase 2 study in T-cell lymphomas – in particular the results from angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL) that is strongly associated with the T follicular helper (TFH) cell phenotype,” said Chip Romp, President and CEO of Secura Bio. “We look forward to developing COPIKTRA beyond its initial indication in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and continuing to build Secura Bio into a world-class biopharmaceutical company with a diverse portfolio of oncology assets.” About nodal T-Follicular Helper Cell Lymphoma Nodal T-follicular helper cell lymphomas (nTFHL) comprise a group of aggressive non-Hodgkin lymphomas that share common genetic, clinical, and cell of origin features. This group of lymphomas originates from a type of white blood cell called a T-follicular helper cell. nTFHLs generally occur in people aged 60 and older and are slightly more common in males. nTFHLs most commonly present with widespread, enlarged, typically painless lymph nodes in the neck, armpit, and/or groin. There are currently no well-established standards of care for patients with relapsed or refractory disease. About COPIKTRA (duvelisib) COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K) and the first US approved dual inhibitor of PI3K-delta and PI3K-gamma pathways, two enzymes known to help support the growth and survival of malignant cells. PI3K signaling may lead to the proliferation of malignant cells and is thought to play a role in the formation and maintenance of a supportive tumor microenvironment. COPIKTRA is indicated in the United States for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. COPIKTRA is also being developed for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status in the United States and is being investigated in combination with other agents through investigator-sponsored studies. Treatment of T-cell lymphomas is a disease category for which COPIKTRA is not currently indicated. For more information on COPIKTRA, please visit www.COPIKTRA.com . Information about duvelisib clinical trials can be found on www.clinicaltrials.gov . IMPORTANT SAFETY INFORMATION ABOUT COPIKTRA WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS See full prescribing information for complete boxed warning Fatal and/or serious infections occurred in 31% (4% fatal) of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected. Fatal and/or serious diarrhea or colitis occurred in 18% (<1% fatal) of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA. Fatal and/or serious cutaneous reactions occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Withhold COPIKTRA. Fatal and/or serious pneumonitis occurred in 5% (<1% fatal) of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA. INDICATIONS AND USAGE COPIKTRA is a kinase inhibitor indicated for the treatment of adult patients with: Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function. Neutropenia: Monitor blood counts. Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ADVERSE REACTIONS The most common adverse reactions (≥20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. DRUG INTERACTIONS CYP3A inducers: Avoid co-administration with strong or moderate CYP3A inducers. CYP3A inhibitors: Monitor for COPIKTRA toxicities when co-administered with strong or moderate CYP3A inhibitors. Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors. CYP3A substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. Please click here to see full Prescribing Information, including Boxed WARNING, for COPIKTRA (duvelisib). About Secura Bio, Inc. Secura Bio is an integrated, commercial-stage pharmaceutical company dedicated to the worldwide development and commercialization of impactful oncology therapies for physicians and their patients. For more information on Secura Bio, please visit https://www.securabio.com/. Investor & Media Contact Will Brown Chief Financial Officer Phone: 619-986-1364 ir@securabio.com Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

$Secura Bio Announces First Patient Dosed in Phase 3 TERZO Study of COPIKTRA® (duvelisib) in Relapsed/Refractory Nodal T-follicular Helper Cell Lymphoma$

临床3期临床2期快速通道上市批准

2025-06-04

·精准药物

【JMC】一种赖氨酸靶向共价 PROTACs，高效降解 PI3Kδ

DOI: 10.1021/acs.jmedchem.5c00408侃侃而言学以致用PROTAC 技术是一种新兴的药物研发策略，与传统抑制剂相比，它能降解目标蛋白，并且具有降低毒性、克服药物抗性等优势。PI3Kδ 是 PI3K/AKT/mTOR 信号通路的关键成员，在白细胞中发挥重要作用，特别是 B 细胞的发育和成熟过程中。而 PI3Kδ 异常表达与则与血液恶性肿瘤、淋巴瘤、自身免疫性疾病密切相关。现有 PI3Kδ 抑制剂存在毒性等局限性问题，开发新的治疗策略成当务之急，比如说 PROTACs 疗法。近日（May 31），西安交通大学医学部药学院在 J. Med. Chem. 上披露了一种基于赖氨酸靶向共价策略的、新型的、高效的 PI3Kδ PROTAC 类降解剂。01PI3Kδ的重要性与现有疗法的局限性 1.1 PI3Kδ的重要性磷脂酰肌醇 3- 激酶（PI3K）是 PI3K/AKT/mTOR 信号通路的关键元素，在细胞生长、增殖和存活中起着重要作用。PI3Kδ 主要表达于白细胞中，参与 B 细胞受体（BCR）信号传导，与 B 细胞的发育和成熟密切相关，其异常表达与血液恶性肿瘤、淋巴瘤和自身免疫性疾病等有很强的关联，因此 PI3Kδ 抑制剂被认为是有前景的治疗血液癌症的药物。 1.2 现有疗法的局限性尽管已有一些 PI3Kδ 抑制剂如 idelalisib、duvelisib 和 umbralisib 等显示出显著的临床疗效，但由于不可避免的毒性问题，它们都受到严格监测，因此开发新的 PI3Kδ 靶向治疗方法成为当前关注的焦点。 1.3 PROTAC 疗法PROTAC 技术可以降解目标蛋白，与传统小分子抑制剂相比，具有独特的作用机制，能够降低毒性并克服药物抗性，近年来在多种蛋白质靶点中得到广泛研究。然而，靶向 PI3Ks 的 PROTACs 研究较少，且已报道的 PROTACs 针对 PI3K 的降解活性和亚型选择性有限，如下图，几乎没有针对 PI3Kδ 亚型的活性报道。因此，研究团队设定了探索 PI3Kδ 靶向降解剂的新方案。02PI3Kδ 靶向降解剂探索 2.1 PI3Kδ 降解剂设计思路研究人员计划开发基于 PROTAC 的 PI3Kδ 降解剂，鉴于 PROTAC 的结构组成特征，共设计了两套方案进行优化：（1）方案1：基于已报道的 PI3Kδ 可逆抑制剂，设计 A 系列分子，如下图，并针对连接子和 E3 连接酶配体进行优化、筛选。（2）方案2：结合结构对接研究，基于PI3Kδ 共价抑制剂，设计 B 系列分子，如下图，并针对连接子、和 E3 连接酶配体进行优化、筛选。 2.2 基于可逆抑制剂的PROTAC探索如下图中，化合物 5 是一个已知的 PI3Kδ 可逆抑制剂，从结构对接模拟可以看出配体与靶标结合口袋的关键相互作用，其中四氢吡喃酰基扩展向溶剂区，因此吡咯烷可作为 PROTAC 连接子的输出位点。为此，研究人员利用不同的连接子和 CRBN、VHL 配体设计了 9 个不同的 PROTACs 分子，如下表。然而，这些化合物对细胞增殖和 PI3Kδ 激酶活性的抑制效果不佳。从结构对接的结果来看，如下图，A 系列分子的 E3 配体无法从 PI3Kδ 的结合口袋中伸出，因此无法有效招募 E3 连接酶。 2.3 基于共价抑制剂的PROTAC探索随后，研究人员转向探索共价抑制剂系列探索，如下图，化合物 6 是已知的 PI3Kδ 共价抑制剂，靶向 K779 残基，IC50 =0.27 nM。如下表，通过调整 PI3Kδ 配体、E3 配体以及不同长度的连接链，对 PROTAC 分子进行筛选和结构-活性关系研究，最终确定了 B 系列中的一些化合物（如 B9、B10、B14 等）表现出较强的 PI3Kδ 降解和抗增殖活性，对 SU-DHL-6 细胞的抗增殖能力优于 idelalisib。 2.4 多维度表征与机制验证随后研究人员针对化合物 B9、B10、B14 进行进一步的评估。如下图，在 SU-DHL-6 细胞中，它们都以浓度依赖方式有效地诱导靶标降解，并且在p-AKT 的水平相应降低。三个化合物对 p110δ 的DC50 值分别为 1.26、5.35、3.98 nM。此外，三个化合物 B9、B10 和 B14 被证实能提高 SU-DHL-6 细胞中 LC3II/LC3I 的比例，推测这会促进细胞内环境中的自噬作用。三个化合物降解 p110δ 的时间过程如下图所示，均表现出时间依赖性降解。总体上，处理期内 B9 和 B14 的 p110δ降解率均高于 B10，因此这两个化合物被选择进一步通过冲洗实验进行评估，如下图。B9、B14 均具有较长的降解效果，相比之下 B14 降解维持时间更长。另一方面，组成 B14 的 VHL-2 比组成 B9 的VHL-1 具有更高的E3连接酶亲和力，导致 p110δ 的泛素化和随后的降解更容易。针对 B14，研究人员构建了两个衍生物 B14-N（非共价）、B14-S（对映异构体，缺少E3连接酶亲和力），以此来对比研究共价和 VHL 有效相互作用对降解效果的影响，如下图。两个衍生物的的细胞抗增殖能力、靶标降解能力显著降低。这些结果表明 B14 对 p110δ 的共价结合和与 VHL 的有效相互作用是降解效果的关键和决定因素。选择性研究：通过对SU-DHL-6 细胞全蛋白质组评估，B14 对 PI3Kδ 的选择性比其他亚型高 70 倍以上，如下图。B14 是一种 PI3Kδ 高选择性降解剂。接下来，研究人员评估了 B14 对 SU-DHL-6 细胞周期进程和凋亡的影响，B9 作为仅次效力化合物，也一同进行检测。B14 能诱导 SU-DHL-6 细胞发生细胞周期阻滞，并促使细胞凋亡，在 0.1 μM 浓度下诱导的细胞凋亡比例显著高于同浓度的 idelalisib。体内抗肿瘤效果：在 SU-DHL-6 异种移植模型中，B14 显示出显著的抗肿瘤效果，以 2 和 10 mg/kg 剂量给药时，肿瘤生长抑制率（TGI）分别为 59.1%和 73.3%，且未引起明显的体重变化和器官损伤，表明其具有良好的体内耐受性。作用机制研究：研究发现 B14 通过与 p110δ 的 Lys779 共价结合，招募 E3 泛素连接酶，形成“E3-PROTAC-PI3Kδ”三元复合物，进而导致 PI3Kδ 的泛素化和降解，且降解过程涉及泛素-蛋白酶体途径。03总结与展望这篇研究首先提出了 PI3Kδ 在疾病治疗中的重要性与现有的局限性，为了解决 PI3Kδ抑制的现有问题，其研究研究思路如下：（1）首先基于 PI3Kδ 可逆抑制剂进行设计 PROTACs 分子，然而对细胞增殖和 PI3Kδ 激酶活性的抑制效果不佳；（2）继而转向基于 PI3Kδ 共价抑制剂设计新型 PROTACs 分子，通过调整优化，筛选出具有更好靶标降解和抗增殖活性的化合物；（3）通过体内/外多维度验证与机制解析，获得了赖氨酸靶向共价 PTOTACs。有效性：成功开发出一系列基于 PROTAC 的 PI3Kδ 降解剂，其中 B14 是首个具有显著降解效果和体内、体外强效抗肿瘤活性的 PI3Kδ 靶向 PROTAC。创新性：采用赖氨酸靶向共价策略为设计 PI3Kδ 靶向 PROTAC 提供了有效的方法，并为开发更有效的 PI3Kδ 靶向 PROTACs 奠定了基础。选择性：B14 对 PI3Kδ 具有选择性降解和抑制活性，对其他 PI3K 亚型（p110α、p110β、p110γ）的降解和抑制效果较弱，显示出较好的选择性这篇研究从可逆策略失败到共价策略成功，通过 SAR优化、活性筛选、机制验证、系统性证明共价 PROTACs 在 PI3Kδ 靶向中的优势，形成了完美的逻辑闭环，也为同类靶点的药物开发提供了指南！很赞。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↓

蛋白降解靶向嵌合体临床结果

100 项与度维利塞相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D10555 D11658	度维利塞	L01XE	DB11952

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
慢性淋巴细胞白血病	美国	Secura Bio, Inc.	2018-09-24
滤泡性淋巴瘤	美国	Secura Bio, Inc.	2018-09-24
小淋巴细胞淋巴瘤	美国	Secura Bio, Inc.	2018-09-24

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
复发性T细胞淋巴瘤	临床3期	捷克	Secura Bio, Inc.	2025-05-19
复发性T细胞淋巴瘤	临床3期	法国	Secura Bio, Inc.	2025-05-19
复发性T细胞淋巴瘤	临床3期	意大利	Secura Bio, Inc.	2025-05-19
复发性T细胞淋巴瘤	临床3期	波兰	Secura Bio, Inc.	2025-05-19
复发性T细胞淋巴瘤	临床3期	西班牙	Secura Bio, Inc.	2025-05-19
复发性T细胞淋巴瘤	临床3期	英国	Secura Bio, Inc.	2025-05-19
惰性非霍奇金淋巴瘤	临床3期	美国	Secura Bio, Inc.	2015-12-01
边缘区B细胞淋巴瘤	临床3期	美国	Secura Bio, Inc.	2015-12-01
复发性 3a 级滤泡性淋巴瘤	临床3期	美国	Secura Bio, Inc.	2015-12-01
CD20阳性滤泡性淋巴瘤	临床3期	澳大利亚	Secura Bio, Inc.	2014-09-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT06522737 (TERZO, EHA2025)	临床3期	具有 TFH 表型的复发性淋巴结外周 T 细胞淋巴瘤 AITL score	124	Duvelisib 75 mg	鏇壓艱糧網夢繭衊鑰鹹(鏇簾遞齋衊鑰網憲繭衊) = 獵積憲壓築範襯艱淵範構鹽夢衊淵鏇艱鏇鏇廠 (構範範鹽憲繭製壓齋積 ) 更多	积极	2025-05-14
NCT05057247 (BURAN, CTgov)	临床2期	晚期头颈部鳞状细胞癌 \| 复发性头颈部鳞状细胞癌 \| 头颈癌转移	26	Duvelisib+Docetaxel	網窪簾膚繭顧醖膚淵範 = 顧範艱鬱壓壓簾構夢壓網構觸膚夢鑰築顧廠醖 (鹽顧鏇餘窪艱壓鑰簾艱, 鹽製鬱繭網蓋膚襯憲襯 ~ 範鏇鑰選願壓壓蓋窪簾) 更多	-	2025-03-05
NCT03372057 (PRIMO, CTgov)	临床2期	外周T细胞淋巴瘤	156	Duvelisib (Dose Optimization Phase: Cohort 1)	糧艱窪範顧蓋膚淵夢窪 = 蓋壓簾築觸製顧糧蓋艱鹹壓膚憲糧製顧襯鏇積 (製襯鬱醖糧獵餘願願餘, 願鏇糧襯廠鏇憲淵製願 ~ 膚觸網憲遞壓鬱構襯齋) 更多	-	2025-02-28
NCT03372057 (PRIMO, CTgov)	临床2期	外周T细胞淋巴瘤	156	Duvelisib (Dose Optimization Phase: Cohort 2)	糧艱窪範顧蓋膚淵夢窪 = 憲鏇構餘夢繭壓餘構廠鹹壓膚憲糧製顧襯鏇積 (製襯鬱醖糧獵餘願願餘, 繭餘餘願憲選蓋夢窪蓋 ~ 製繭壓觸網壓遞繭艱壓) 更多	-	2025-02-28
ASH2024	N/A	外周T细胞淋巴瘤	-	Duvelisib 75 mg BID + Romidepsin 10 mg/m2	窪鑰築糧積簾觸積窪廠(網顧窪襯製構製糧鹽糧) = anemia (n=3) 糧齋鹽糧鑰夢願鬱糧窪 (繭製築廠鬱餘選獵襯選 ) 更多	-	2024-12-09
ASH2024 人工标引	临床1期	T细胞淋巴瘤	49	Ruxolitinib 20mg BID + Duvelisib 25mg BID	顧觸繭觸網齋願餘鹹淵(觸窪鏇繭願鬱製窪醖網) = 鏇獵壓選憲鏇鏇淵壓簾襯憲獵構壓糧餘繭壓鹽 (鑰構膚醖膚繭蓋獵構願 ) 更多	积极	2024-12-08
3065A (ASH2024)	临床1期	外周T细胞淋巴瘤	14	Duvelisib 25 mg	夢範遞壓齋壓觸願鹹願(艱蓋憲繭襯鹽鏇膚顧衊) = 製顧壓壓壓鬱餘鏇繭鏇構網餘遞築製鹹觸範網 (齋蓋願觸衊鏇蓋鏇網淵, 6.3 ~ NE) 更多	积极	2024-12-08
3065A (ASH2024)	临床1期	外周T细胞淋巴瘤	14	Duvelisib 50 mg	夢範遞壓齋壓觸願鹹願(艱蓋憲繭襯鹽鏇膚顧衊) = 壓遞築遞簾餘衊願製築構網餘遞築製鹹觸範網 (齋蓋願觸衊鏇蓋鏇網淵, 6.3 ~ NE) 更多	积极	2024-12-08
NCT04038359 (TEMPO, CTgov)	临床2期	难治性惰性非霍奇金淋巴瘤 \| 惰性非霍奇金淋巴瘤	103	Duvelisib (Duvelisib, Continuous and Intermittent Dosing)	淵醖築齋積範齋鏇窪鹽 = 廠鹽繭顧鑰觸鑰淵願構獵製範製壓醖蓋衊廠範 (製窪遞齋廠廠製憲窪齋, 齋選範壓網醖選鑰構顧 ~ 窪廠窪觸築餘鏇構蓋鹽) 更多	-	2024-09-19
NCT04038359 (TEMPO, CTgov)	临床2期	难治性惰性非霍奇金淋巴瘤 \| 惰性非霍奇金淋巴瘤	103	Duvelisib (Duvelisib, Intermittent Dosing)	淵醖築齋積範齋鏇窪鹽 = 製醖壓積築淵簾餘築選獵製範製壓醖蓋衊廠範 (製窪遞齋廠廠製憲窪齋, 齋壓範顧蓋鹽構憲鑰壓 ~ 襯鹽餘顧壓襯襯網鏇膚) 更多	-	2024-09-19
NCT03961672 (CTgov)	临床2期	复发性慢性淋巴细胞白血病 \| 难治性慢性淋巴细胞白血病 \| 难治性小淋巴细胞淋巴瘤	15	Duvelisib	選壓廠廠廠膚膚鹽積壓 = 獵艱繭獵壓繭構襯蓋鑰蓋夢鬱遞鹹齋憲願積齋 (鹽選窪積壓構衊壓築壓, 鏇鬱衊願鑰壓願襯願鏇 ~ 糧顧餘窪廠壓築憲製顧) 更多	-	2024-08-07
NCT02783625 (phase 1b/2a trial, Pubmed)	临床1/2期	复发性T细胞淋巴瘤 PI3K-δ	66	Duvelisib + Romidepsin	鏇積築膚醖築簾艱網製(餘齋蓋艱齋蓋網顧齋觸) = 齋襯夢夢艱網遞醖網餘構鑰選觸顧壓淵製願鹽 (齋觸繭淵遞膚願簾膚鑰 ) 更多	积极	2024-06-17
NCT02783625 (phase 1b/2a trial, Pubmed)	临床1/2期	复发性T细胞淋巴瘤 PI3K-δ	66	Duvelisib + Bortezomib	鏇積築膚醖築簾艱網製(餘齋蓋艱齋蓋網顧齋觸) = 積窪繭鬱醖選糧繭齋鏇構鑰選觸顧壓淵製願鹽 (齋觸繭淵遞膚願簾膚鑰 ) 更多	积极	2024-06-17
NCT05057247 (BURAN, ASCO2024)	临床2期	转移性头颈部鳞状细胞癌 HPV+ \| PI3K	26	Duvelisib	糧膚築選顧淵壓鏇齋繭(構廠襯衊襯糧鑰遞構淵) = 獵艱觸衊觸憲鹽憲憲鬱廠構蓋壓齋齋餘獵鏇襯 (構壓鑰構夢獵齋鹽製鬱, 6.8 ~ 40.7) 更多	积极	2024-05-24