Patients with metastatic bladder cancer are usually treated with chemotherapy. If their cancers do not progress after chemotherapy, they can be enrolled into this study and receive a standard-of-care immunotherapy medication named avelumab plus a study drug named copanlisib.

开始日期2024-11-01

申办/合作机构

VA Office of Research and Development

[+1]

NCT06218667 / Withdrawn临床1/2期IIT

CHARIOT: a Phase 1b/2 Study of Androgen Deprivation Therapy and Copanlisib in High-Risk Localized Prostate Cancer Patients Prior to Radical Prostatectomy

The researchers are doing this study to find out whether copanlisib in combination with degarelix, given before standard surgical treatment (radical prostatectomy), is a safe and effective treatment that causes few or mild side effects for people who have localized high-risk prostate cancer.

开始日期2024-01-11

申办/合作机构

Memorial Sloan Kettering Cancer Center

NCT05082025 / Active, not recruiting临床2期IIT

Phase 2 Study of PI3K Inhibitor Copanlisib in Combination With Fulvestrant in Selected ER+ and/or PR+ Cancers With PI3K (PIK3CA, PIK3R1) and/or PTEN Alterations

The purpose of this study is to evaluate the efficacy and safety of copanlisib in combination with fulvestrant in advanced hormone receptor-positive (HR+) solid tumors harboring alterations that activate the Phosphatidylinositol-3 kinase (PI3K) pathway.

开始日期2022-09-27

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与盐酸可泮利塞相关的临床结果

登录后查看更多信息

100 项与盐酸可泮利塞相关的转化医学

登录后查看更多信息

100 项与盐酸可泮利塞相关的专利（医药）

登录后查看更多信息

172

项与盐酸可泮利塞相关的文献（医药）

2024-12-04·JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY

Characterization of Anticancer Drug Protomers Using Electrospray Ionization and Ion Mobility Spectrometry–Mass Spectrometry

Article

作者: Riedel, Jerome ; Volmer, Dietrich A. ; Safferthal, Marc ; Basuri, Pallab ; Kovacevic, Borislav ; Schorr, Pascal ; Pagel, Kevin

We used electrospray ionization and ion mobility spectrometry-mass spectrometry to detect and characterize the three anticancer drugs palbociclib, copanlisib, and olaparib. Ion mobility-mass spectrometry and density functional theory revealed that these compounds generate isomers during ionization (protomers) due to the presence of multiple protonation sites within their chemical structures. Our work has implications for understanding the solution- and gas-phase chemistry of these molecules during spray-based ionization processes.

2024-12-01·FITOTERAPIA

Depside and depsidone-rich hydroalcoholic extract, resourced from the lichen Parmelinella wallichiana (Taylor) Elix & Hale selectively restricts Non-Small Cell Lung Cancer by modulating p53, FOXO1 and PALLADIN genes

Article

作者: Ray, Ribhu ; Saha, Saparja ; Paul, Santanu

The non-specificity of contemporary cancer therapeutics has enticed us to develop safer, anticancer alternatives from natural resources. Lichens are unique natural entities which have long been neglected for explorations in cancer therapy, despite their vast potential. Our present study aims to investigate the anti-cancer potential of a wild lichen Parmelinella wallichiana. The anti-proliferative efficacy of the lichen extracts were screened through MTT assay against a panel of cell lines and the potent hydroalcoholic extract was selected for further evaluation against the most sensitive lung-cancer cell line A549 by implementing a wide range of microscopic and flow cytometric applications. The observations suggest that the extract could selectively induce apoptosis by augmenting ROS and disrupting the mitochondrial membrane potentiality. It was also found that the lichen-induced apoptosis was regulated by two crucial tumor suppressor genes, FOXO1, and p53, along with cell cycle inhibitor p21 which ultimately resulted in robust apoptosis through the up-regulation of pro-apoptotic BAX expression. Moreover, the extract also restricted the cancer progression by down-regulating the PALLADIN expression. Further, an LC-MS-based metabolomic profile highlighted a number of depsides, depsidones and dibenzofurans, which included atranorin, physodalic acid, salazinic acid, constictic acid and usnic acid. Then, an in silico docking with these lichen-derived metabolites against the PI3Kα receptor predicted these compounds has a binding affinity close to a standard PI3Kα inhibitor copanlisib. The study concludes that the extract restricts lung cancer possibly through the PI3Kα/FOXO1 axis and thus Parmelinella wallichiana represents a potential resource for anti-lung cancer drug development in future.

2024-12-01·Molecular diversity

Computational discovery of novel FYN kinase inhibitors: a cheminformatics and machine learning-driven approach to targeted cancer and neurodegenerative therapy

Article

作者: Gopal, Dhanushya ; Muthuraj, Rajesh ; Chandrasekaran, Jaikanth ; Balaya, Rex Devasahayam Arokia ; Kanekar, Saptami ; Ahmed, Iqrar

In this study, we explored the potential of novel inhibitors for FYN kinase, a critical target in cancer and neurodegenerative disorders, by integrating advanced cheminformatics, machine learning, and molecular simulation techniques. Our approach involved analyzing key interactions for FYN inhibition using established multi-kinase inhibitors such as Staurosporine, Dasatinib, and Saracatinib. We utilized ECFP4 circular fingerprints and the t-SNE machine learning algorithm to compare molecular similarities between FDA-approved drugs and known clinical trial inhibitors. This led to the identification of potential inhibitors, including Afatinib, Copanlisib, and Vandetanib. Using the DrugSpaceX platform, we generated a vast library of 72,196 analogues from these leads, which after careful refinement, resulted in 6008 promising candidates. Subsequent clustering identified 48 analogues with significant similarity to known inhibitors. Notably, two candidates derived from Vandetanib, DE27123047 and DE27123035, exhibited strong docking affinities and stable binding in molecular dynamics simulations. These candidates showed high potential as effective FYN kinase inhibitors, as evidenced by MMGBSA calculations and MCE-18 scores exceeding 50. Additionally, our exploration into their molecular architecture revealed potential modification sites on the quinazolin-4-amine scaffold, suggesting opportunities for strategic alterations to enhance activity and optimize ADME properties. Our research is a pioneering effort in drug discovery, unveiling novel candidates for FYN inhibition and demonstrating the efficacy of a multi-layered computational strategy. The molecular insights gained provide a pathway for strategic refinements and future experimental validations, setting a new direction in targeted drug development against diseases involving FYN kinase.

项与盐酸可泮利塞相关的新闻（医药）

2024-08-28

·精准药物

【Nature Cancer】First-in-class 的 EGFR 和 PI3K选择性抑制剂MTX-531

尽管精准肿瘤学取得了巨大进步，但适应性耐药机制限制了分子靶向药物的长期有效性。在这里，评估了 MTX-531 的药理学特征，该药物经过计算机辅助设计，选择性地靶向两个关键耐药驱动基因：表皮生长因子受体(EGFR)和磷脂酰肌醇激酶 (PI3K)。MTX-531 对这两个靶标均表现出低纳摩尔效力，并通过共晶结构分析高度特异性机制。MTX-531单一疗法导致PDX模型的肿瘤消退。MTX-531 与 MEK或 KRAS-G12C 抑制剂的组合导致BRAF突变或KRAS突变结直肠癌 PDX 模型的持久消退，导致中位生存期显著增加。MTX-531为MEKanistic Therapeutics和密歇根大学共同研发，目前处于IND阶段。 1. 背景介绍对个体癌症的基因组测序和多种小分子激酶抑制剂的批准使精准肿瘤学取得了革命性的进步。然而，适应性耐药机制会损害激酶靶向疗法的长期有效性，因此需要联合用药策略。施用多种激酶抑制剂的传统组合方法会增加脱靶毒性的风险，并且难以实现对预期靶标的平衡和完全抑制。另一种方法是合理设计抑制多种耐药驱动因素的小分子，这些小分子具有足够的选择性以避免不可接受的毒性。表皮生长因子受体 (EGFR) 和磷脂酰肌醇 3-OH 激酶 (PI3K) 成为这一概念的潜在共靶向候选者，因为这些致癌激酶可驱动多种人类癌症的适应性耐药。在头颈鳞状细胞癌 (HNSCC) 中，已知 EGFR 和 PI3K 各自介导对另一种抑制剂的耐药。西妥昔单抗是唯一被批准用于治疗这种疾病的激酶靶向疗法，其临床活性并不高。在高达 80% 的 HNSCC 中发现了导致 PI3K–mTOR（雷帕霉素哺乳动物靶标）信号通路失调的分子突变，并导致对 EGFR 抑制的抵抗力增强。PI3K 领域的治疗失败归因于不可接受的毒性，部分原因是需要高暴露以引发单一治疗活性。PI3Kα 抑制剂 alpelisib (Piqray) 因其针对PIK3CA突变的晚期乳腺癌的活性而成为该靶标中唯一获批的临床药物。alpelisib 和泛 PI3K 抑制剂 copanlisib 均可恢复 HNSCC 临床前模型中对西妥昔单抗的敏感性。然而，当这些 PI3K 抑制剂与西妥昔单抗在临床上联合使用时，益处并没有超过风险。设计一种有效的 PI3K 抑制剂，具有改善的治疗指数，并且不易出现 EGFR 介导的适应性耐药，这是一个高度未满足的临床需求。 EGFR 和 PI3K 通路信号传导也与KRAS突变和BRAF突变结直肠癌 (CRC) 对 RAS-MAPK 通路干预的适应性耐药有关。虽然单独使用 EGFR 抑制剂并不适用于治疗KRAS突变疾病，但临床前研究结果支持其与 PI3K–mTOR 或 MEK（MAPK 激酶）抑制剂联合使用来治疗KRAS突变 CRC。在BRAF突变 CRC 的情况下，负反馈激活环路响应 BRAF 的抑制而激活 EGFR，导致 MAPK 和 PI3K 通路信号传导重新激活。分别针对 BRAF 和 EGFR 的encorafenib和西妥昔单抗组合已成为治疗BRAF V600转移性 CRC 的标准治疗方法。在该方案中进一步添加 PI3K 抑制剂 alpelisib 可提供额外的功效，但代价是毒性增加。 PI3K 在致癌信号传导中的核心作用、以及与其治疗靶向相关的毒性挑战让人想起 RAS 所面临的问题。几十年来，RAS 一直被认为是不可成药的，直到 Shokat 及其同事的突破性发现报告了 KRAS-G12C 共价小分子抑制剂的设计。本研究旨在设计一种 PI3K 抑制剂，该抑制剂比之前报道的此类靶标分子具有更好的耐受性，并且对 PI3K 和 EGFR 具有高度选择性。这种药物治疗KRAS突变癌症的组合潜力值得注意。 2. MTX-531 是一种有效的选择性 EGFR 和 PI3K 抑制剂基于结构的药物设计策得到分子MTX-531（图1a）。基于对分别与 EGFR 和 PI3Kγ 结合的 NVP-AEE788　和 omipalisib 的已知结构特征的分析，小分子被合理设计为以选择性和同时的方式抑制 EGFR 和 PI3K（图1b ）。NVP-AEE788 稠合环的 6 位指向溶剂，而 omipalisib 中的该位置则延伸至 PI3Kγ 的三磷酸腺苷 (ATP) 口袋和特异性口袋的背面。利用 EGFR 和 PI3Kγ 之间喹唑啉核心的这种翻转结合模式，通过计算机辅助设计了这两个酶家族的有效且具有选择性的双重抑制剂。图 1. a，MTX-531的化学结构。b ，NVP-AEE788 与 EGFR 结合（左）和 omipalisib 与 PI3Kγ 结合（右）的结构特征。补充表1和2概述了 MTX-531 的关键结构-活性关系发现。与 MTX-531 结合合的 EGFR 和 PI3Kγ 的共晶体结构证实了 MTX-531 与每个靶标的假定反向结合模式。MTX-531中喹唑啉环的1 位与EGFR的M793骨架酰胺形成关键氢键（图1c）。图 1. c，EGFR 与 MTX-531 (PDB:8SC7 ) 的共晶体结构。左为二级结构；右图是 MTX-531 从 ATP 结合位点与 EGFR 结合的视图。 4 位的取代基与 K745 和 T790 脂肪族侧链形成的疏水口袋契合，而 6 位的亲水基团面向外，面向 EGFR 的溶剂可及区域。MTX-531的1位与PI3Kγ的V882的主链酰胺形成氢键（图1d）。图 1. d，PI3Kγ 与 MTX-531 (PDB: 8SC8 ) 共晶体结构。左为二级结构；右图是 MTX-531 从 ATP 结合位点与 PI3Kγ 结合的视图。与 EGFR 的相互作用不同，MTX-531 的6 位的基团结合在分别由 Y867 和 K833 的亲水羟基和胺基产生的 PI3K 亲水区域内。这里描述的所有研究都是使用 ( R )-异构体进行的，与 ( S )-异构体相比，它对 EGFR 的效力强约 100 倍，对抗 PI3K 的效力弱约 10 倍。总的来说，观察到的结合模式与这些异构体效力差异一致。( S )-异构体中 MTX-531 的甲基取代基朝向 EGFR 的空间限制区域，从而阻碍结合。 MTX-531 对纯化的 EGFR 和 PI3Kα 表现出低纳摩尔效力，半数最大抑制浓度 (IC50 ) 值分别为 15 nM 和 6.4 nM（表1）。表 1. MTX-531 以及参比抑制剂对 HER 和 PI3K 家族成员的生化抑制效力。参比分子 omipalisib 和 NVP-AEE788 的抑制 PI3K 和 EGFR 功效分别比 MTX-531 强约 30 倍至 50 倍。两种分子的临床开发均已终止，可能是受到其毒性特征的影响。MTX-531 对多个 PI3K 家族成员和 mTOR 的强大效力揭示了其生化特征与临床批准的 alpelisib (Piqray) 和 copanlisib (Aliqopa) 明显不同（表1）。Copanlisib 和 MTX-531 具有泛 PI3K 抑制特性，而 alpelisib 的 PI3Kα 抑制效果比其他 PI3K 亚型强 1-3 个数量级。与 PI3Kα 相比，MTX-531 对 mTOR 的抑制效力仅低约 15 倍，这是其与 alpelisib 和 copanlisib 的区别特征。随后针对超过 400 种蛋白质和脂质激酶的激酶组选择性评估表明，MTX-531 对 EGFR和 PI3K 家族成员具有极好的选择性（图1e）。图 1. e ，MTX-531的激酶选择性。在 10 µM 浓度下，只有 HER 家族以外的 9 种蛋白激酶被抑制超过 80%。MTX-531 针对这些非靶向激酶的测定显示，对除MELK(IC50 178 nM）之外的所有激酶均无显著抑制（IC50 ≥ 0.5 μM）。MELK 的脱靶抑制被认为是无关紧要的，因为 MTX-531 在浓度高达 5 µM 时对 MELK 没有细胞作用。对大量参与临床药物不良反应的非激酶靶标（ n = 86）进行筛选，发现只有四种蛋白与 MTX-531 结合，IC 50 < 10 μM。在已知具有PIK3CA突变 (H1047R) 的 CAL-33 HNSCC 模型中，处理 2 小时后，MTX-531 对 EGFR、PI3K 和 mTOR 表现出浓度依赖性抑制作用，通过较低水平的磷酸化 (p)EGFR、蛋白激酶 B (Akt) 和真核翻译起始因子 4E 结合蛋白 1 进行测量（ 4E-BP1)(图2a)。这些靶标的平衡细胞抑制反映在可比较的 IC 50值（约 300 nM）中，证明 MTX-531 在抑制 EGFR 和 PI3K-mTOR 信号传导方面具有同等效力。此外，当 MTX-531 浓度接近 1 µM 时，通过切割聚（ADP-核糖）聚合酶（PARP）的表达测量，观察到细胞凋亡的显著诱导。较短的潜伏期显示出途径抑制的时间依赖性增加。1 µM 的 MTX-531 在添加药物后 15 分钟内最大程度地抑制 CAL-33 细胞中的 pAkt T308表达（抑制 97%）。15分钟后pEGFR表达的抑制是显著的（减少65%），但没有达到图2a中2小时时看到的抑制程度（90%）。图 2：MTX-531 在 HNSCC CAL-33 和 CAL-27 模型中共同靶向细胞 EGFR 和 PI3K 信号传导。在小鼠口腔癌 (MOC1细胞) 模型中对 PI3K 信号传导的有效抑制提供了细胞证据，表明 MTX-531 与突变酶一样有效对抗野生型 PI3K。进一步评估了 MOC1 和 CAL-27 细胞（它们是 PIK3CA 的野生型）MTX-531 对 pHER3 表达的影响。CAL-27 模型中的 pHER3 水平（EGFR 扩增）响应 MTX-531 治疗而显著降低，pEGFR 和 pHER2 水平也显著降低。MTX-531 对 MOC1 细胞中激活的 HER 家族成员表达的影响相对减弱，而 MOC1 细胞的 EGFR 没有已知的畸变。 3. MTX-531 单一疗法可导致 HNSCC 异种移植物消退 MTX-531 表现出良好的药物样特征，支持其先进的临床前开发，并且在小鼠中表现出高（约 80%）的口服生物利用度，使其有利于口服给药研究。MTX-531 的早期单药体内评估重点是确定其对 HNSCC 异种移植物的治疗活性，因为 EGFR 和 PI3K 在这种疾病的进展中都发挥着重要作用。EGFR 在大约 90% 的 HNSCC 中过度表达，而 PI3K-mTOR 信号传导的广泛激活也发生在 >80% 的病例中。单次口服剂量 MTX-531 后切除的 CAL-33 肿瘤的药效学评估显示 EGFR 和 PI3K-mTOR 通路信号传导的时间依赖性抑制（图3）。图 3：MTX-531 抑制 HNSCC PDX 模型中的 EGFR 和 PI3K-mTOR 信号传导以及肿瘤生长。在PDX模型中对MTX-531与Erlotinib和alpelisib的组合进行了头对头评估（图3e）。MTX-531 单药治疗使肿瘤平均消退 70%，而Erlotinib-alpelisib 联合治疗组未观察到肿瘤消退。MTX-531 每天给药 100 mg*kg-1，在所有 HNSCC PDX 研究中均具有良好的耐受性。 4. MTX-531 增强 CRC 中的 MEK 抑制作用针对 EGFR（西妥昔单抗）、PI3K（alpelisib）和下游 MAPK 通路靶点（encorafenib 或 Trametinib）的三重组合虽然在科学上是合理的，但已被证明具有挑战性，部分原因是耐受性差。由于 MTX-531 靶向这些试验中三个关键信号传导节点中的两个，因此研究了将其与 MEK 抑制剂曲美替尼 (Trametinib) 联合治疗KRAS突变和BRAF突变 CRC PDX 模型的治疗效果。NCI CN0375-F725 (KRAS-A136T) 异种移植物对曲美替尼或 MTX-531 的单药治疗没有反应（图4a）。然而，联合治疗组的客观缓解率达到了 80%，动物的中位生存率提高了 467%。图 4：MTX-531 与 MEK 抑制剂曲美替尼的组合导致BRAF突变和KRAS突变 CRC 模型回归。 MTX-531和曲美替尼的组合在BRAF V600E突变的CRC PDX模型(UM-CRC 14-929)中也有效(图4b )。尽管曲美替尼没有活性，但 MTX-531 单一疗法导致大多数动物的肿瘤停滞。MTX-531 和曲美替尼 (Trametinib) 联合使用可进一步提高疗效，部分缓解率为 40%。对联合组切除肿瘤中激酶表达的药效学评估显示，pS6 水平显著降低 97%，这与单药性能改善的疗效一致（图4b ）。在单药治疗研究中采用的MTX-531每日给药方案（100 mg*kg-1）中添加1 mg*kg-1曲美替尼具有良好的耐受性并且不会导致体重减轻。 5. MTX-531 与 KRAS-G12C 抑制具有协同作用直接靶向 KRAS-G12C 的药物对KRAS G12C突变型 CRC 的活性有限，部分原因是 EGFR 介导的细胞外信号调节激酶 (ERK) 信号重新激活，导致针对 KRAS-G12C 和 EGFR 的药物进行联合试验。然而，由其他受体酪氨酸激酶 (RTK) 驱动的继发耐药机制或 mTOR 信号传导的上调限制了对该组合策略的反应的持久性。基于其 EGFR-PI3K-mTOR 抑制特性，预计 MTX-531 与 KRAS-G12C 抑制剂联合使用将有效。这一假设得到了 KRAS-G12C 抑制剂 sotorasib 与 MTX-531 组合在携带KRAS G12C突变 CRC 或胰腺肿瘤的小鼠中产生的数据的支持。NCI 135848-042-T CRC 异种移植物还含有mTOR (S2215F) 和ERBB2 (S310F) 突变，由于对照动物体重减轻超过 10%，因此给药时间缩短至 10 天。尽管如此，在联合治疗组中观察到了肿瘤停滞，而与任一单一药物的反应不活跃相反（图5a，左）。B8239 CRC 异种移植物也在PIK3CA (H1047R) 中发生突变，对单独使用 sotorasib 有一定程度的敏感性，并且对单药 MTX-531 的反应相对较高，其客观反应率为 40%（图5a ，中）。然而，用 sotorasib 和 MTX-531 联合治疗 B8239 荷瘤小鼠导致部分消退的发生率为 100%。sotorasib 和 MTX-531 的组合对 MIA PaCa-2 异种移植物最有效，所有小鼠均显示完全消退，超过单药 sotorasib 所见的完全消退发生率 40%（图5a ，右）。图 5：MTX-531 和 sotorasib 的组合可导致KRAS G12C突变型 CRC 和胰腺肿瘤的消退。 MTX-531 在 B8324 中进行了进一步评估，B8324 是一种 CRC KRAS G12C突变型PIK3CA E542K突变型 PDX 模型，由接受 sotorasib 和帕尼单抗(panitumumab，EGFR)联合治疗方案进展后的患者建立。B8324 异种移植物对单独的 sotorasib 治疗无效，与临床进展一致，但对 MTX-531 单药治疗敏感，如 60% 的客观缓解率所反映的（图5b）。MTX-531 和 sotorasib 的组合具有非常好的耐受性，导致该组 40% 的动物出现 100% 的消退发生率和完全消退。从切除的肿瘤显示细胞凋亡显著增加（通过切割的 PARP 表达增加来测量）以及 PI3K-mTOR 信号传导的强烈抑制（分别通过 pAkt 和 pp70S6K 表达的抑制 >90% 和 >80% 反映）（图5b ，右）。相比之下，MTX-531 导致KRAS – PIK3CA突变模型中 pEGFR 表达适度降低 14%。 6. MTX-531 不会导致小鼠高血糖由于 PI3Kα 在胰岛素信号传导中的核心作用，高血糖是 PI3K 抑制剂最常见的靶向副作用。因为MTX-531是一种泛PI3K抑制剂，所以以治疗水平给药的小鼠没有表现出血糖水平显着升高的观察是出乎意料的（图6a ）。与不存在高血糖一致，MTX-531治疗对血液胰岛素水平也没有影响，这与alpelisib不同，alpelisib引起血浆葡萄糖和胰岛素水平显着升高（图6b）。这一结果在测试扩大的 PI3K 抑制剂组（包括临床批准的和失败的药物）后得到证实（图6c）。MTX-531剂量增加至150 mg*kg-1也未能诱导高血糖。Cantley 及其同事报告了在用 PI3K 抑制剂治疗的肿瘤中，全身葡萄糖-胰岛素反馈在介导 PI3K 信号传导重新激活中的作用。他们证明小鼠携带同源Kras基因；Tp53 ；Pdx-Cre (KPC) 胰腺肿瘤对 alpelisib 没有反应，除非采用生酮饮食。这里，当在 KPC 模型中直接比较 MTX-531 与 alpelisib 的抗肿瘤活性时，两种分子在培养细胞中均在 10-100 nM 范围内抑制 PI3K 信号传导，其中 alpelisib 的效力强约 5 倍。然而，在携带 KPC 肿瘤的小鼠中，观察到它们的活性存在显著差异。所有对照和alpelisib处理的小鼠在给药完成2周之前均被安乐死，反映了该肿瘤模型的高度侵袭性（图6d ）。相反，在 MTX-531 治疗的小鼠中观察到肿瘤停滞。MTX-531 对中位生存期的影响（增加 215%）与用 alpelisib 治疗并采用生酮饮食的小鼠所显示的影响相当。此外，CAL-33和KPC肿瘤中的胰岛素水平响应alplelisib而非MTX-531而显著升高，这与胰岛素循环水平的差异一致（图6e）。总的来说，这些研究表明 MTX-531 可能不太容易受到胰岛素介导的反馈机制的影响，从而损害 PI3K 抑制剂的抗肿瘤活性。对 KPC 肿瘤和参与维持葡萄糖稳态的正常组织（即肝脏和骨骼肌）中 pAkt 表达的评估证实，MTX-531 在给药 2 小时内抑制肿瘤和正常组织中的 PI3K。图 6：MTX-531 在治疗剂量水平下不会导致高血糖。 7. PPARγ 激活是 MTX-531 的独特功能作者推测，用 MTX-531 治疗的小鼠没有出现高血糖，是因为该分子具有作为核激素受体 PPARγ 激动剂的独特能力。时间分辨荧光共振能量转移 (TR-FRET) 竞争性结合测定显示 MTX-531 是 PPARγ 的弱激动剂 (IC50 = 2.5 μM)，并且在浓度高达 100 μM 时对 PPARα 和 PPARδ 无活性（图7 a-b )。在 293H 细胞中进行的报告基因测定中评估了 MTX-531 对 PPARγ 活性的细胞内影响，结果显示针对 PPARγ 的激动剂活性（EC 50 = 3.4 μM；图7a ，右），与罗格列酮(Rosiglitazone，PPARγ)相比，其效力显著较低（ EC50 = 14 nM）。通过逆转录 (RT)-qPCR 在处理的 3T3-L1 细胞中测量参与诱导脂肪细胞分化的 PPARγ 靶基因的表达，为 MTX-531 和 PPARγ 之间的功能相互作用提供进一步的证据。将3T3-L1前脂肪细胞在含有MTX-531（10μM）或罗格列酮（1μM）的分化诱导培养基中培养8或24小时，然后评估脂肪细胞标志物PPARγ（由Pparg编码）、脂蛋白脂肪酶（由Lpl编码）和脂联素（由Adipoq编码）的基因表达（图7c）。已知这些标记物会因罗格列酮的反应而上调。两种化合物对PPARγ的最大诱导范围从两倍到四倍，这为 MTX-531 作为 PPARγ 激动剂的能力提供了进一步的支持。在蛋白质水平上，PPARγ1和PPARγ2表达水平的上调程度再次与罗格列酮和MTX-531之间的显著效力差异一致（图7c ，右）。图 7：MTX-531 作为 PPARγ 激动剂。接下来，作者试图生成 MTX-531 与 PPARγ 结合的 X 射线晶体结构，为它们的相互作用提供结构证据。PPARγ 和 MTX-531 的三维复合物从衍射至 1.9-Å 分辨率的晶体中解析出来（图7d）。化合物结合位点处清晰的电子密度揭示了整个化合物的结合，从而允许配体的明确放置（图7e）。最终解析的结构包含两个 PPARγ 分子（链 A 和 B）和一个与链 B 结合的 MTX-531 分子。已知 PPARγ 配体结合区域是一个大的、大部分为疏水性的空腔，能够结合多种小分子物质。MTX-531的喹唑啉核心似乎位于由L330和R288的脂肪族侧链堆叠形成的PPARγ口袋中（图7d）。MTX-531 中 6 位喹唑啉核心的官能团结合在与结合罗格列酮的正构口袋不同的位点（图7f ）。 8. 讨论 MTX-531经过合理设计，选择性地抑制EGFR和PI3K。EGFR 和 PI3Kγ 之间喹唑啉核心的反向结合模式是 MTX-531 设计中的一个重要元素，它对两个预期靶标均显示出低纳摩尔效力。Knight 及其同事首先报告了设计酪氨酸和磷酸肌醇激酶双重抑制剂的可行性（10.1038/nchembio.117）。通过迭代药物化学和 X 射线晶体学，他们鉴定出采用单一结合模式来高效抑制 PI3K 和多种酪氨酸激酶的分子。相比之下，MTX-531 是一种具有选择性的 ATP 竞争性蛋白激酶抑制剂。在所测试的 432 种激酶中，只有 4 种被发现表现出 IC 50 < 1 μM，并且没有一种激酶的 IC 50 值在 MTX-531 针对 EGFR 的靶向效力的 10 倍之内（IC 50 ≈ 15 nM）。据报道，Erlotinib针对 EGFR 的效力大约比 MTX-531 强 1 个数量级，但是据报道，其针对至少 20 种脱靶激酶的 IC 50 < 1 μM。值得注意的是，据报道，当已批准的 PI3K 抑制剂 alpelisib 或 copanlisib 在临床试验中与西妥昔单抗联合使用时，会出现高血糖问题。MTX-531 不会导致小鼠 PI3K 抑制剂诱导的高血糖这一发现令人鼓舞，因为这种副作用对于小鼠和人类都很常见。在临床试验中，高血糖已成为证明因全身葡萄糖稳态破坏而有效抑制 PI3K 的替代生物标志物。有趣的是，据报道，与泛 PI3K 抑制剂相比，PI3Kα 选择性抑制剂具有改善的临床前治疗窗，因为它们降低了高血糖的倾向。然而，这两类 PI3K 抑制剂都会导致血糖水平升高，而 MTX-531 则不会。作者提出假设是 MTX-531 对 PPARγ 的激动活性可以抵消 PI3K 驱动的高血糖。PPARγ激动剂通常用于治疗2型糖尿病，以增加对胰岛素的敏感性。与此一致的是，Powis 等报道了噻唑烷二酮吡格列酮可预防 PI3K 抑制剂 PX-866 引起的高血糖。MTX-531 是一种泛 PI3K 抑制剂，独特地不会引起高血糖。与这一观察结果一致，用 MTX-531 治疗的小鼠不需要采用生酮饮食来积极对抗高度侵袭性的 KPC 肿瘤，并且可能不太容易受到胰岛素介导的 PI3K 信号重新激活的影响。最终，MTX-531 将需要临床测试来验证其良好的临床前毒性特征。如果这种分子被证明在患者中具有良好的耐受性，那么它在单药和联合治疗中的多功能性将提供广泛的开发策略，随着联合候选药物的出现，这些策略将继续发展。MTX-531 具有同时选择性抑制 EGFR、PI3K 和 mTOR 的独特能力，说明了合理地计算机辅助药物设计针对单个分子中多种适应性耐药机制的能力。参考：10.1038/s43018-024-00781-6 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↓

临床申请临床1期

2024-08-09

·fda.gov

FDA grants accelerated approval to copanlisib for relapsed follicular lymphoma

On September 14, 2017, the U.S. Food and Drug Administration granted accelerated approval to copanlisib (ALIQOPA, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies. Approval was based on efficacy results in 104 patients with relapsed follicular lymphoma enrolled in an open-label, single-arm, multicenter, phase 2 trial. Patients received 0.8 mg/kg or 60 mg of copanlisib by intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle. The objective response rate was 58.7% (95% CI: 48.6%-68.2%) with an estimated median response duration of 12.2 months (range, 0+ to 22.6 months). The complete response rate was 14.4% and partial response rate was 44.2%. The safety population included 168 patients with follicular lymphoma and other hematologic malignancies treated with the recommended copanlisib dosing regimen. Common adverse reactions in greater than 20% of patients include hyperglycemia, diarrhea, fatigue, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia. The most common grade 3-4 adverse reactions include hyperglycemia, leukopenia, hypertension, neutropenia, and lower respiratory tract infections. Serious non-infectious pneumonitis occurred in 6% of patients. The recommended copanlisib dose is 60 mg administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Full dosing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209936s000lbl.pdf FDA previously granted orphan drug and fast track designation for copanlisib. As a condition of accelerated approval, a randomized controlled trial will be required to verify the clinical benefit of copanlisib. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). Follow the Oncology Center of Excellence on Twitter@FDAOncology. Check out recent approvals at the OCE’s new podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.), available at www.fda.gov/DISCO. Content current as of: 09/14/2017 09/14/2017 Resources for Information | Approved Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description Oncology (Cancer)/Hematologic Malignancies Approval Notifications Ongoing | Cancer Accelerated Approvals Verified Clinical Benefit | Cancer Accelerated Approvals Withdrawn | Cancer Accelerated Approvals Other | Cancer Accelerated Approvals Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description

加速审批临床结果快速通道上市批准孤儿药

2024-08-08

·echemi

Regulatory Challenges of Gene Therapy and Cancer Drugs: Industry Trends Behind the Withdrawal of Zydelig and FDA's Response

In 2022, Gilead announced that it would voluntarily withdraw Zydelig from the U.S. market for two lymphoma treatments, a full six years after it suspended the trial due to patient deaths. A Gilead spokesperson clarified that the withdrawal was not due to safety concerns, but rather because of insurmountable obstacles to recruiting subjects for additional research trials required by the FDA. Nevertheless, Zydelig retains its eligibility for the treatment of chronic lymphocytic leukemia and remains on the market for patients. Notably, the withdrawal of Zydelig coincides with the withdrawal of several other PI3K inhibitors used to treat follicular lymphoma: Secura Bio's duvelisib (trade name Copiktra) withdrawn in December 2021, TG's umbralisib (trade name Ukoniq) withdrawn in 2022 (here may be a clerical error, read "February" or adjusted to another month), Bayer's copanlisib (trade name Aliqopa) also withdrew from the market in November 2023. Together, these events outline an industry trend. A study published in JAMA Internal Medicine reveals an interesting data point: Before Gilead decided to withdraw some uses of Zydelig from the U.S. market, its global sales had reached a staggering $842 million. This reflects the wide application and high recognition of the drug in the market, although it ultimately failed to fully meet all expectations for various reasons. Interestingly, the pharmaceutical industry sometimes employs a series of ingenious strategies to speed up the process of bringing a product to market. Eli Lilly, for example, successfully used all four avenues of acceleration to bring oncology product Lartruvo to market in 2016. The key clinical data for the product is based only on the results of a trial involving 133 patients, and while the results showed a possible positive impact on survival outcomes for sarcoma, a cancer that affects muscles and other soft tissues, the specific effect on slowing cancer growth is unclear. However, just over two years later, a larger study revealed that Lartruvo had no significant impact on patient survival, and Eli Lilly had to withdraw it from the market. Despite this, Lartruvo still managed to achieve a whopping $500 million in sales during its short market life. Among the many drugs approved for accelerated marketing, oncology products have become the hardest hit by ineffective drugs. However, as the development of therapies continues to deepen and progress, new questions continue to emerge and are presented to the FDA. In particular, advanced therapies represented by cell and gene therapies, when they meet with the accelerated approval system, have brought unprecedented challenges to this "old revolution". Given the complexity of cell and gene therapies and the relative lack of understanding of their safety, once ineffective advanced therapies are released to the market, the consequences and impacts will be far beyond the scope of small molecule ineffective drugs. For example, the tragic death of a three-year-old boy in a clinical trial of Pfizer's fordadistrogene movaparvovec, a gene therapy for Duchenne muscular dystrophy, highlights the shortcomings and limitations of researchers in predicting the potential for serious adverse events. As vectors of ssRNA (single stranded RNA), viruses (such as AAV) play a critical role in gene therapy, but can also cause a series of serious adverse events including cardiopulmonary failure, myocarditis, thrombotic microangiopathy, and acute liver failure. These potential risks have forced the FDA to be more cautious and rigorous in approving gene therapies. Speaking at the annual meeting of the American Society for Gene and Cell Therapy, CBER director Peter Marks said speeding up the withdrawal of approved gene therapies could be easier and faster than for small-molecule therapies. At the same time, he stressed that "accelerated approval of gene therapy is not a get-out-of-jail-free ticket." The FDA will not hesitate to withdraw accelerated approval of rare disease gene therapies if they fail subsequent confirmatory trials." Marks further points out that the "one-size-fits-all" nature of gene therapy makes confirmatory studies easier to follow and monitor patients over time. It also makes for greater clarity and clarity on the question of whether to withdraw gene therapy. In contrast, there may be more controversy and disagreement in the decision process of withdrawing cancer therapy. Marks, however, said the FDA would only withdraw gene therapy if it was clear that the patient benefit was likely to be "minimal" but the side effects were significant. He cited a case in which Bluebird Bio's sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) caused patients to develop myelodysplastic syndrome and leukemia during treatment. The product was approved by the FDA in December 2023 with a boxed warning about hematologic malignancies. Marks said it is unclear whether these malignancies are related to the preconditioning regimen associated with Lyfgenia treatment, the underlying disease, or the gene therapy itself. In addition, the case of drug manufacturers refusing to voluntarily withdraw the market is not unique in the history of FDA accelerated approval. Everything from the withdrawal of Makena, a drug that reduced the risk of preterm birth, after 12 years on the market, to the legal battle between Pepaxto and the FDA highlights the complexity and seriousness of the issue. In the face of these challenges, FDA has to seek the support of legislation to strengthen its regulatory power and capability. Fortunately, the introduction of the FDORA (Comprehensive Food and Drug Reform Act) bill provides the FDA with greater flexibility and autonomy to act without public hearings.

上市批准基因疗法

100 项与盐酸可泮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
-	盐酸可泮利塞	L01XX61	DB12483

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
滤泡性淋巴瘤	美国	Bayer HealthCare Pharmaceuticals, Inc.	2017-09-14

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
惰性B细胞非霍奇金淋巴瘤	申请上市	加拿大	Bayer, Inc.	2021-12-01
小淋巴细胞淋巴瘤	申请上市	加拿大	Bayer, Inc.	2021-12-01
巨球蛋白血症	申请上市	加拿大	Bayer, Inc.	2021-12-01
边缘区B细胞淋巴瘤	申请上市	欧盟	Bayer AG	2021-06-12
非霍奇金淋巴瘤	申请上市	中国	Bayer AG	2021-03-10
惰性非霍奇金淋巴瘤	临床3期	美国	Bayer Pharma AG	2016-01-06
惰性非霍奇金淋巴瘤	临床3期	美国	拜耳医药保健有限公司	2016-01-06
惰性非霍奇金淋巴瘤	临床3期	阿根廷	拜耳医药保健有限公司	2016-01-06
惰性非霍奇金淋巴瘤	临床3期	阿根廷	Bayer Pharma AG	2016-01-06
惰性非霍奇金淋巴瘤	临床3期	澳大利亚	Bayer Pharma AG	2016-01-06

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


NCT02626455 (CHRONOS-4, CTgov)	临床3期	复发性惰性非霍奇金淋巴瘤	551	Copa (SRI: Copa+R-B 45 mg)	衊蓋廠艱蓋範夢製選糧(窪繭網網製構膚夢鏇遞) = 鏇醖夢襯齋艱膚糧艱願齋鏇鬱襯餘窪衊鑰鑰鏇 (齋構餘鏇網淵觸衊製艱, 範選鏇構淵網積窪繭夢 ~ 製獵夢鑰憲窪簾製蓋構) 更多	-	2024-12-11
				Copa (SRI: Copa+R-B 60 mg (Excluding Subjects From Japan))	衊蓋廠艱蓋範夢製選糧(窪繭網網製構膚夢鏇遞) = 齋築鹽蓋艱鹽襯衊鹹窪齋鏇鬱襯餘窪衊鑰鑰鏇 (齋構餘鏇網淵觸衊製艱, 構鑰廠襯淵廠憲壓壓鏇 ~ 築壓襯簾選膚蓋鏇願艱) 更多
NCT02626455 (CHRONOS-4, Pubmed \| Blood Adv) 人工标引	临床3期	惰性B细胞非霍奇金淋巴瘤	524	Copanlisib rituximabbendamustine	衊築膚艱觸窪顧鹹觸壓(壓壓獵夢製鏇選蓋糧範) = 夢窪襯窪繭齋膚遞觸艱鏇鹹艱淵簾壓鬱淵積壓 (鹹遞簾餘醖遞廠鹽遞艱, 24.4 ~ 38.6)	不佳	2024-09-24
				Placebo rituximabbendamustine	衊築膚艱觸窪顧鹹觸壓(壓壓獵夢製鏇選蓋糧範) = 夢衊膚窪膚構襯鏇製壓鏇鹹艱淵簾壓鬱淵積壓 (鹹遞簾餘醖遞廠鹽遞艱, 27.8 ~ 42.8)
NCT03939897 (CTgov)	临床1期	复发性乳腺癌 \| HR阳性乳腺腺癌 \| 转移性乳腺癌 ... 更多	24	Copanlisib+Fulvestrant+Abemaciclib (Phase I Part A Dose Level 1 (Copanlisib, Abemaciclib, Fulvestrant))	鬱蓋選餘壓窪顧簾構壓(淵糧夢積築壓醖範鬱壓) = 憲艱膚衊範鑰觸鹹膚夢蓋簾鏇鹹獵壓鏇選簾衊 (繭製網蓋簾襯構衊觸顧, 廠範鏇齋襯選窪築顧範 ~ 積餘簾憲簾遞獵鬱夢壓) 更多	-	2024-07-30
				Copanlisib+Fulvestrant+Abemaciclib (Phase I Part A Dose Level 2 (Copanlisib, Abemaciclib, Fulvestrant))	鬱蓋選餘壓窪顧簾構壓(淵糧夢積築壓醖範鬱壓) = 遞壓顧淵顧蓋繭簾選網蓋簾鏇鹹獵壓鏇選簾衊 (繭製網蓋簾襯構衊觸顧, 窪襯憲憲構鏇觸衊蓋製 ~ 獵壓獵獵膚醖積壓夢選) 更多
NCT04933617 (CTgov)	临床1期	高级别B细胞淋巴瘤 \| T细胞/组织细胞丰富的大B细胞淋巴瘤 \| 伯基特淋巴瘤	8	copanlisib (All Participants)	齋鹹積顧淵獵夢齋膚製(願獵積選齋糧憲製憲觸) = 願鹹鹹鹹顧齋鬱鏇襯襯簾積鬱繭網淵膚衊餘網 (蓋襯選鬱艱鏇網範築壓, 鹹顧艱壓鬱積膚襯廠窪 ~ 壓壓築積醖膚憲齋鬱餘)	-	2024-07-09
				Copanlisib (Dose Escalation: Arm 1, Dose Level 1, Original: 30mg Copanlisib)	憲齋網糧繭醖鬱構蓋齋(繭襯糧壓鏇醖鑰顧製廠) = 衊壓廠願積範選積膚網繭繭醖淵蓋廠憲膚廠顧 (壓鬱壓築鑰鏇選構艱廠, 選築顧簾範衊積蓋構膚 ~ 獵築觸顧築鏇窪壓壓鬱) 更多
NCT03484819 (ASH2023)	临床2期	纵隔大b细胞淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	106	Copanlisib	願醖範鬱網壓觸餘鑰膚(齋獵獵齋襯壓簾鬱鑰窪) = 鬱衊網鹽餘鹹繭膚衊鹹遞範網膚鬱夢蓋願鬱觸 (遞膚餘網衊膚衊鬱夢範, 5 ~ 57)	-	2023-12-11
NCT04433182 (FIL Copa-RB, ASH2023)	临床2期	复发性弥漫性大B细胞淋巴瘤	37	Copanlisib + Rituximab + Bendamustine	蓋襯遞願淵簾廠鹹遞願(積夢齋廠積鏇網蓋夢蓋) = 窪餘獵顧觸鏇顧顧遞壓廠窪網壓簾壓製顧餘廠 (襯鏇網選鹽醖壓築鹹構, 13.6 ~ 38.5) 更多	-	2023-12-09
ASH2023	临床1期	非霍奇金淋巴瘤 \| 里氏综合症	25	Copanlisib+Nivolumab	鏇觸鬱壓糧廠壓餘鏇醖(簾範鹹鹽觸糧膚鑰遞網) = 製選憲壓鹹築築構網廠蓋製網築遞繭築選憲餘 (窪鬱顧鬱範糧醖鏇顧鹽 ) 更多	-	2023-12-09
NCT04572763 (ASH2023)	临床1期	复发性弥漫性大B细胞淋巴瘤	12	Copanlisib	願淵糧廠範膚糧襯衊築(窪餘齋艱積簾艱築遞鏇) = 齋願蓋襯艱廠獵鏇壓鏇鏇憲壓鏇顧齋夢鏇襯壓 (襯糧糧鏇製網憲壓餘壓 ) 更多	-	2023-12-09
ASH2023	临床2期	滤泡性淋巴瘤	28	Copanlisib 60mg + Rituximab 375mg	觸製鑰觸衊糧願鏇膚壓(窪艱壓鹹艱製選艱艱廠) = 壓鏇繭獵齋襯鏇淵餘鑰蓋鑰積廠蓋窪艱顧壓觸 (鏇艱窪壓憲糧鑰醖鹹齋 ) 更多	-	2023-12-09
NCT02369016 (CHRONOS-2, CTgov)	临床3期	难治性惰性非霍奇金淋巴瘤	25	Copanlisib (Copanlisib (BAY80-6946, Aliqopa))	觸憲顧築簾獵齋鬱遞築(顧鹽艱醖鹹蓋範窪願壓) = 鏇衊壓觸膚鬱選齋齋襯鏇選築鑰廠築艱膚蓋艱 (願餘齋廠顧艱築餘積憲, 顧鬱窪蓋壓膚鏇廠醖衊 ~ 鹽餘壓獵艱齋鹽顧繭構) 更多	-	2023-11-18
				placebo (Placebo)	觸憲顧築簾獵齋鬱遞築(顧鹽艱醖鹹蓋範窪願壓) = 淵夢齋淵壓鬱膚糧遞範鏇選築鑰廠築艱膚蓋艱 (願餘齋廠顧艱築餘積憲, 壓憲繭簾獵積網壓顧膚 ~ 範鏇鑰壓願醖鹽餘齋餘) 更多