A Randomized Double-Blind, Placebo-Controlled, Multicenter Study of CI-994 Capsules Plus Gemcitabine Infusion Versus Placebo Capsules Plus Gemcitabine Infusion as Second-Line Treatment of Patients With Advanced Nonsmall Cell Lung Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether gemcitabine plus CI-994 is more effective than gemcitabine alone for non-small cell lung cancer.
PURPOSE: Randomized phase III trial to compare the effectiveness of gemcitabine with or without CI-994 in treating patients who have advanced non-small cell lung cancer.

开始日期1999-12-01

申办/合作机构

Pfizer Inc.

NCT00004861

/ Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of CI-994 Capsules Plus Gemcitabine Infusion Versus Placebo Capsules Plus Gemcitabine Infusion in the Treatment of Patients With Advanced Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug or giving drugs in different ways may kill more tumor cells.
PURPOSE: Randomized phase II trial to compare the effectiveness of gemcitabine with or without CI-994 in treating patients who have advanced pancreatic cancer.

开始日期1999-10-01

申办/合作机构

Pfizer Inc.

NCT00005624

/ Completed临床2期IIT

A Multicenter Phase 2 Study of Oral N-Acetyl Dinaline (CI-994) in the Treatment of Patients With Advanced Myeloma

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase II trial to study the effectiveness of CI-994 in treating patients who have advanced myeloma.

开始日期1997-08-01

申办/合作机构

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+2]

100 项与乙酰地那林相关的临床结果

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100 项与乙酰地那林相关的转化医学

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100 项与乙酰地那林相关的专利（医药）

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项与乙酰地那林相关的文献（医药）

2025-08-01·EJHaem

Targeted Degradation of Class 1 HDACs With PROTACs is Highly Effective at Inducing DLBCL Cell Death

Article

作者: Cowley, Shaun M. ; Alraddadi, Abdullah ; Jones, Donald J. L. ; Cao, Thong H. ; Hodgkinson, James T. ; Smalley, Joshua P. ; Al‐Mansour, Fares ; Saleh, Anes ; Jayne, Sandrine ; He, Buwei ; Dyer, Martin ; Macip, Salvador ; Alzahrani, Wael

ABSTRACT:

Despite the good options for the management of Diffuse large B‐cell lymphoma (DLBCL), a significant percentage of patients either do not respond to current treatments or relapse after a short time. Thus, a wider palette of targeted therapeutic strategies is needed. Histone deacetylases (HDACs) inhibitors have shown promising responses in B‐cell malignancies, but their off‐target effects limit their efficiency. Here, we investigated the use of novel targeted therapeutics against class I HDACs to specifically induce cell death in DLBCL cells. We show that a proteolysis targeting chimera (PROTAC) that combined HDAC inhibitor CI‐994 and an IAP ligand had a strong effect in killing different DLBCL cell lines, being more effective in doing so than CI‐994 on its own. Moreover, we show that this was concomitant with the induction of DNA damage and apoptosis. A proteomics screen showed that the mechanism of induction of cell death by this PROTAC likely depends on the simultaneous activation of pro‐apoptotic proteins (such as PARP‐1, PDCD6IP, DAPk1, TP53BP1, and CACYBP) and the inhibition of pro‐survival pathways. We conclude that eliminating class I HDACs with specific PROTACs could be an effective and precise strategy for treating DLBCL that should be further tested for their potential clinical relevance.Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

2025-07-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design and synthesis of pyridine-based benzamides as potent HDAC3 inhibitors as an armament against breast cancer with in vivo validation

Article

作者: Begum, Darakhshan ; Regula, Sanjeev ; Routholla, Ganesh ; Ghosh, Balaram ; Biswas, Swati ; Adhikari, Nilanjan ; Pulya, Sravani ; Patel, Tarun ; Banerjee, Suvankar ; Himaja, Ambati

Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines. The most promising molecule in series 7c exhibited ∼47-fold HDAC3 selectivity over HDAC2 isoform. Compound 7c induced apoptosis and cell cycle arrest in the G2/M phase in the 4T1 cell line. Moreover, compound 7c yielded a good in vivo pharmacokinetic profile. Notably, compound 7c markedly reduced tumor growth in the 4T1-Luc breast cancer xenograft model in female Balb/c mice. Compound 7c also upregulated apoptotic proteins namely caspase-3, caspase-7, and cytochrome c, and downregulated Bcl-2. The antitumor potential of compound 7c was further justified by the downregulation of EGFR and Ki-67 through Western blot analysis. Nevertheless, the HDAC3 inhibitory potency of compound 7c depicted strong and stable binding interaction at the HDAC3 active site. These findings validated that compound 7c is a promising HDAC3 inhibitor that can be further investigated for clinical translation to achieve emerging breast cancer therapeutics.

2025-04-01·JOURNAL OF NEUROSCIENCE METHODS

A method for HDAC activity screening in postmortem human brain. A proof-of-concept study with antipsychotics

Article

作者: Callado, Luis F ; Rivero, Guadalupe ; Martínez-Peula, Oihane ; Muguruza, Carolina ; Ramos-Miguel, Alfredo ; Meana, J Javier

BACKGROUND:

Histone deacetylase (HDAC) density and activity are altered in different brain disorders. Antipsychotic drugs (APs) might modulate HDAC activity in brains of schizophrenia subjects.

NEW METHOD:

HDAC activity assay amenable for enzyme kinetics and HDAC inhibitor (HDACi) screening studies in postmortem human brain samples.

RESULTS:

The optimization and characterization work involved several steps. The nucleosolic subcellular fraction and total protein amount needed for an optimal HDAC activity on Boc-Lys(Ac)-AMC substrate were characterized. Signal-to-noise ratio (1.8) and Z-score values (0.82) were indicators of the assay quality. Inhibition studies with non-selective (belinostat, vorinostat, valproic acid) and selective (apicidin, MS275, romidepsin, tacedinaline and EX527) HDACis showed that the optimized assay detected class I HDAC activity. The obtained IC50 values were similar to those previously reported, proving the assay reliability. We used the optimized assay to study the effect of APs on HDAC activity. Inhibition studies with APs in postmortem human brain, together with enzyme kinetic studies in brains of rats chronically treated with APs observed no modulation of class I HDAC activity.

COMPARISON WITH EXISTING METHODS:

This study describes the optimization of a reliable and cost efficient HDAC activity assay for its use in postmortem human brain samples. The assay does not depend on antibody specificity and it is valid for enzyme kinetic studies and for the screening of new potential class I HDACis.

CONCLUSIONS:

We optimized and characterized an assay to measure HDAC activity in postmortem human brain samples. We did not observe any modulatory effect of APs on HDAC activity.

项与乙酰地那林相关的新闻（医药）

2025-03-29

·学术经纬

Nature | 研究揭示髓母细胞瘤常见突变的致癌机制

撰文 | 吴大荣责编 | 周叶斌理解突变如何导致蛋白质-蛋白质相互作用的改变，以及这些改变如何驱动肿瘤的发生，仍癌症研究一个重要的未解决问题。KBTBD4是一种CULLIN3-RING E3泛素连接酶复合物的底物受体，其突变在髓母细胞瘤中频繁出现，而这些突变使KBTBD4 获得功能，从而诱导转录辅阻遏物CoREST5的异常降解。近日，Brian B. Liau 和合作伙伴们在 Nature 上发表题为 Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations 文章，揭示了功能获得性E3突变和分子胶降解剂UM171之间基于形状互补性的吻合机制，证明HDAC1/2抑制剂可以阻断突变型KBTBD4–HDAC1界面和KBTBD4突变型髓母细胞瘤细胞的增殖。在泛素-蛋白酶体系统中，人类疾病突变早已知道会损害几种E3泛素连接酶的功能。相比之下，促进底物蛋白异常降解的E3功能获得性突变最近被发现。尽管有通过改变连接酶稳定性或调节性导致非计划的底物泛素化的多形态（hypermorphic）E3突变病例，但直接诱导新底物参与和降解的E3突变，即“新降解”，是E3连接酶失调的新例子。KBTBD4（一种 CULLIN3-RING E3 连接酶的底物受体）的癌症突变主要发生在 KELCH 重复 β 螺旋桨 2b-2c 环的热点中，具有相当大的分子多样性，包括1-5 个氨基酸的插入或缺失（insertion or deletion）以及点替换。值得注意的是，KBTBD4 还参与了 UM171 的机制，后者是一种诱导 CoREST 降解的造血干细胞扩增小分子激动剂。为揭示UM171 和 KBTBD4 癌症突变之间惊人的相似机制，该团队做了几个关键实验：深度突变扫描：绘制了KBTBD4 癌症热点的突变图，揭示了插入和替换可以促进功能获得的不同偏好以及热点相互作用中有关的关键残基。KBTBD4的癌症突变通过直接靶向HDAC1/2，促进CoREST（一种控制染色质可及性和转录的复合物）的降解，这种降解会改变表观遗传程序，进而改变转录程序，促进癌细胞干细胞的增加，从而驱动肿瘤发生。冷冻电子显微镜分析：对与 LSD1–HDAC1–CoREST （LHC 综合体）结合的两个不同 KBTBD4 癌症突变体的低温电子显微镜分析表明，KBTBD4 同型二聚体与 HDAC1 不对称地结合，具有两个 KELCH 重复的β-螺旋结构域。髓母细胞瘤突变稳定了 HDAC1 和其中一个 KBTBD4 β-螺旋之间的界面，使一个庞大的侧链插入 HDAC1 活性位点。最近的研究表明，KBTBD4作用机制与UM171 相吻合， UM171 通过促进 CoREST 的泛素化和降解在表型上和髓母细胞瘤中KBTBD4突变相似。在相关的研究中，研究人员确定UM171的加入稳定了KBTBD4-LHC 复合物的结构，并证明了UM171充当分子胶以诱导 E3 和 HDAC1 之间的复合物形成。比较KBTBD4-UM171-LHC 复合物与两个和LHC 结合的 KBTBD4突变体之间的结构，明显看出两机制的吻合，如图1所示。通过该机制，分子胶和癌症突变可以补充和优化 E3 连接酶和 HDAC1 之间较差的蛋白质-蛋白质界面，从而驱动它们的结合。图1，左-UM171（黄色和蓝色棒）、突变型KBTBD4- Tyr312 侧链（青色和红色棒）以及另一突变型 KBTBD4- Arg312 侧链（绿色和蓝色棒）在 HDAC1 活性位点口袋处（粉色）的比较。深紫色棒显示了两个苯丙氨酸残基，勾勒出 HDAC1 活性位点通道的入口。右- UM171（黄色和蓝色棒状图）与突变型KBTBD4的 2b-2c 环状图的比较，其中 KBTBD4–UM171–HDAC1 结构通过 HDAC1 与突变型 KBTBD4–HDAC1 结构叠加，界面处关键残基的侧链以红色棒状标示。药物干预实验：结构和深度突变扫描结果表明KBTBD4 MB 突变体通过去乙酰化酶活性位点的热点相互作用直接与 HDAC1/2 结合，从而促进 CoREST 降解。这些观察结果意味着HDAC1/2 活性位点抑制剂可以在空间上阻断突变连接酶的结合，从而阻断其致癌功能。突变型KBTBD4-HDAC1 与与辛二酰苯胺羟肟酸 (SAHA) 结合的 HDAC2 的叠加分析支持这一观点，即 HDAC1/2 抑制剂和插入的精氨酸残基可能会发生位置冲突。用SAHA，CI-994（一种 2-氨基苯甲酰胺衍生的抑制剂）和RBC1HI（新型 HDAC1/HDAC2 抑制剂，Regenacy Brain I 类 HDAC 抑制剂）进行试验，证明了这三种抑制剂可以保全由两种突变KBTBD4-P 和 KBTBD4-PR 表达引起的 CoREST 降解，如图2所示。图2，左-SAHA（黄色）与突变型KBTBD4 2b-2c 环（绿色）中央精氨酸残基之间的位置冲突。右-细胞增殖实验， DMSO，SAHA，CI-994或 RBC1HI与带有标示的KBTBD4 突变体之间的荧光素信号（纵轴），两次生物学重复了解突变是如何实现新蛋白质-蛋白质相互作用（PPI）的分子机制不仅对于理解疾病病因至关重要，而且对于指导治疗方法（例如分子胶和 PPI 抑制剂）用化学调节这些界面也至关重要。该研究表明，KBTBD4的癌症突变通过与HDAC1的相互作用促进CoREST的降解，且可以通过小分子药物进行调节，这为针对KBTBD4突变的治疗提供了新的思路。未来的研究应集中在扩展对其他相关突变的研究，探索其在不同类型癌症中的作用；开发针对KBTBD4突变的特异性治疗策略，例如分子胶UM171和HDAC1/2抑制剂；进一步研究KBTBD4与其他蛋白质的相互作用，以全面理解其在肿瘤发生中的角色。撰文责编制作排版 | 车洁校对 | uu延伸阅读*本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系shiyu@curekids.cn。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。▼滑动查看更多▼原文摘要（Abstract）Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma3, the most common embryonal brain tumour in children4. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST5. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3-neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions.DOI: 10.1038/s41586-024-08533-3👇点击此处，直达原文

蛋白降解靶向嵌合体

2023-02-22

·生物谷

JITC：乙酰地那林与抗CD47抗体组合使用有望治疗MYC扩增的髓母细胞

MYC扩增的髓母细胞（MYC amplified medulloblastoma）通常是一种致命的脑癌形式。在一项新的研究中，来自美国科罗拉多大学安舒茨医学校区和德国癌症联盟杜塞尔多夫大学医院的研究人 MYC扩增的髓母细胞（MYC amplified medulloblastoma）通常是一种致命的脑癌形式。在一项新的研究中，来自美国科罗拉多大学安舒茨医学校区和德国癌症联盟杜塞尔多夫大学医院的研究人员发现一种药物组合可能为被诊断为MYC扩增的髓母细胞瘤的儿童患者提供更好的预后。相关研究结果于2023年1月13日在线发表在Journal for ImmunoTherapy of Cancer期刊上，论文标题为“Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation”。论文共同通讯作者、科罗拉多大学医学院的Siddhartha Mitra博士说，“一个称为MYC的癌基因在这些肿瘤中扩增，使得它们非常容易复发。此外，它扩散到大脑其他区域和脊柱的风险更大。这种癌症的五年生存率不到45%。我们想为这些儿童患者发现更好的治疗方案。” Mitra及其研究团队发现，两种已在其他实体瘤中通过I期安全试验的药物一起使用时，对这种肿瘤有重大影响。通过使用表观遗传药物乙酰地那林（tacedinaline，CI-994），Mitra团队发现除了使肿瘤生长外，MYC还将肿瘤隐藏在体内的各种免疫细胞之外而不被看到。他们能够解禁所谓的阻止免疫系统中的巨噬细胞吞噬肿瘤的“不吃我通路”。 CI-994在MYC驱动的髓母细胞瘤细胞系中诱导细胞凋亡并下调MYC表达。图片来自Journal for ImmunoTherapy of Cancer, 2023, doi:10.1136/jitc-2022-005871。 Mitra说，“当我们用乙酰地那林解禁这些通路，然后加入抗CD47抗体---即一种使巨噬细胞成为超级吞噬者的药物，肿瘤变得对巨噬细胞非常有吸引力，吸引后者去吞噬被解开的肿瘤。这本质上就是利用身体自身的免疫系统，让它快速启动，很像医学版的吃豆人（PacMan）。” Mitra说，虽然像化疗这样的传统疗法以前靶向肿瘤生长通路，但是这是第一次在这些类型的破坏性脑瘤中靶向免疫逃避通路。 Mitra说，“传统的成人癌症药物在儿童身上效果不好，因为儿童仍在发育，他们的正常细胞分裂速度很快。这种药物组合不仅有可能帮助最大限度地减少传统癌症治疗对儿童的负面影响，而且还能让被诊断为MYC扩增的髓母细胞瘤患者有更好的生存机会。” Mitra说，下一步将是一项临床试验，以确定这种治疗的短期和长期效果。（生物谷 Bioon.com）参考资料： Viktoria Marquardt et al. Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation. Journal for ImmunoTherapy of Cancer, 2023, doi:10.1136/jitc-2022-005871.

临床1期临床结果AACR会议申请上市

2022-06-20

·生物谷

PNAS：抗癌药物或能发挥机体表观遗传记忆的辅助作用

来自瑞士洛桑联邦理工学院等机构的科学家们通过研究揭示了如何重新定向抗癌药物来改善机体记忆，其或许能通过支持细胞读取对记忆非常重要的基因的能力来实现。近日，一篇发表在国际杂志Proceedings of the National Academy of Sciences上题为“The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intracellular communication after learning”的研究报告中，来自瑞士洛桑联邦理工学院等机构的科学家们通过研究揭示了如何重新定向抗癌药物来改善机体记忆，其或许能通过支持细胞读取对记忆非常重要的基因的能力来实现，目前研究人员在小鼠机体中揭示了这种药物的表观遗传学机制。抗癌药物或能发挥机体表观遗传记忆的辅助作用。图片来源：Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2116797119 如果你害怕蜘蛛，你或许会很快从一种药物中获益从而提高机体解除蜘蛛恐惧症的能力，同时还不会产生任何不良的副作用。组蛋白去乙酰化酶抑制剂（HDACis，Histone deacetylase inhibitors）是一种特殊的化学化合物，其能作为抵御多种癌症的化疗的辅助剂，这种药物能增强化疗的作用效率，当没有化疗的作用时其并不会产生可观察到的效应；在过去10年里，HDACis能作为一种认知增强剂广泛用于精神病学和神经学的动物模型研究中，这种药物能改善多种动物机体的大脑记忆并不会出现明显的副作用，鉴于这种药物的作用是全身性的，这一点或许让科学家们感到非常困惑。如今，研究人员发现HDACis或许能作为表观遗传记忆的辅助工具，即其能支持细胞读取对大脑突触可塑性非常重要的基因的能力，从而改善神经元之间的交流沟通。研究者Johannes Graff说道，这种药物能支持非常特殊的基因，即那些能参与机体学习的基因，且并不会影响其它很多基因的表达，比如可能会存在会产生不需要的副作用的基因。文章中，研究人员分析了与记忆储存和衰退相关的表观遗传学机制，随后他们转向小鼠来研究其机体中的HDACis，研究人员将小鼠暴露于电击下，即称之为巴甫洛夫（恐惧）条件反射范式，这是一种联想记忆的测试。在没有药物的情况下，小鼠学到的东西很少，而使用该药物后，其记忆力增加了一倍。图片来源：https://www.pnas.org/doi/full/10.1073/pnas.2116797119 研究者指出，这种药物只有在积极学习某些东西时才会增强大脑记忆，其能够加速已经在运动中学习的基因，比如，一旦你已经开始滑雪了就更容易加速，而不是从站立的位置来加速。此外研究人员还发现，这种药物能通过诱导支持学习的表观遗传学修饰来直接作用于表观基因组，染色质是一种DNA和蛋白质组装的复合体，主要会将长链DNA分子包装成更紧凑的结构，突触可塑性基因的转录需要染色质的可及性才能够发生，的确，利用先进的测序技术，科学家们就能观察到，染色质的可及性能在对突触交流非常重要的特定基因中被增强。这些研究发现非常重要，因为多种HDACis已经获批用于治疗癌症患者，这意味着其能在人类机体中被安全使用，如今其能被重新定向用于人类的临床试验从而增强机体大脑的记忆；目前研究人员正在欧洲开展两项临床试验，其中一项旨在增强人们克服对蜘蛛的恐惧，另一项则旨在改善阿尔兹海默病患者的记忆。综上，本文研究结果表明，系统性的HDACi给药或许能放大大脑区域性的特定过程，而这些过程能被学习自然诱导。（生物谷Bioon.com）原始出处： Allison M. Burns， Mélissa Farinelli-Scharly,Sandrine Hugues-Ascery, et al. The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intracellular communication after learning, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2116797119

100 项与乙酰地那林相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D05988	-	-	DB12291

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
晚期非小细胞肺癌	临床3期	美国	Pfizer Inc.	1999-12-01
晚期非小细胞肺癌	临床3期	加拿大	Pfizer Inc.	1999-12-01
胰腺癌	临床2期	美国	Pfizer Inc.	1999-10-01
胰腺癌	临床2期	加拿大	Pfizer Inc.	1999-10-01
多发性骨髓瘤	临床2期	美国	Parke-Davis & Co. Ltd.	1997-08-01
乳腺癌	临床2期	美国	Pfizer Inc.	-
结直肠癌	临床1期	美国	Pfizer Inc.	-