作者: Lima-Júnior, Roberto César Pereira ; Nobre, Lívia Maria Soares ; Silva, Raiza Lima ; Pereira, Anamaria Falcão ; Alencar, Nylane Maria Nunes ; Cajado, Aurilene Gomes ; Lopes, Marina Helena ; Ferreira, Luana Maria Moura ; Alves, Ana Paula Negreiros Nunes ; Wong, Deysi Viviana Tenazoa ; Quispe, Celia Choquenaira ; Rangel, Gisele Fátima Pinheiro ; Paguada, Ana Lizeth Padilha ; Quintela, Lízias Claudia Sampaio ; Ferreira, Kayanny Queiroz ; Silva, Jussara Matyelle Rodrigues

Irinotecan-based anticancer therapy induces intestinal mucositis, increasing the risk of sepsis and patient death. The phosphoinositide 3-kinases (PI3K) are involved in cancer and inflammatory diseases, but their role in intestinal mucositis remains unknown. C57BL/6 male mice received vehicle (1 % DMSO, 10 ml/kg, p.o.), irinotecan alone or in combination with AS-605240 (a PI3Kγ inhibitor, 10 mg/kg, p.o.) or GSK2269557 (a PI3Kδ inhibitor, 3 mg/kg, p.o.). Histopathology, inflammatory markers, and diarrhea were assessed to evaluate mucositis. The antitumor effect was evaluated in mice inoculated with the Mc-38 colorectal cancer cell line. PI3Kγ inhibition attenuated irinotecan-induced intestinal injury, as evidenced by improved villus/crypt ratio. PI3Kγ inhibition also caused milder neutrophil accumulation, reduced expression of Tlr2, Tlr4, and Tlr9, and decreased levels of interleukin-1β and -6, as well as attenuated immunofluorescence for F4/80, a macrophage marker, and the regulatory T cell transcription factor FOXP3 (P < 0.05 vs. irinotecan). Additionally, AS-605240 prevented goblet cell loss and attenuated diarrhea. Moreover, PI3Kγ inhibition combined with irinotecan showed no synergistic anticancer effects. In contrast, PI3Kδ blockade did not prevent the development of mucositis but rather enhanced neutrophil accumulation in the intestine. PI3Kγ inhibition attenuates chemotherapy-associated intestinal mucositis without compromising the anticancer efficacy of irinotecan. However, selective inhibition of PI3Kδ exacerbates the inflammatory response and tissue damage.

2025-11-01·JOURNAL OF CONTROLLED RELEASE

Immunomodulatory microbubbles targeting integrin αvβ3 in combination with immunotherapy for the theranostic of anaplastic thyroid cancer in mice

Article

作者: Bo, Zhang ; Jiajia, Tang ; Xuejiao, Yu ; Zhe, Sun ; Yang, Du ; Taulier, Nicolas ; Xinyi, Liu ; Xinyao, Liu ; Liangkai, Wang ; Jiaojiao, Ma

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid malignancy and currently lacks effective treatment options. While anti-PD1 therapy has shown remarkable clinical results in some cases, only a subset of ATC patients responds to it. Eganelisib (IPI549), a highly selective PI3Kγ inhibitor, can alleviate the tumor immunosuppressive state by reducing the proportion of M2-like tumor associated macrophages, partially overcoming patient resistance to anti-PD1 therapy and synergizing with its efficacy. However, the dose-dependent hepatotoxicity of IPI549 limits its utility in combination immunotherapy. To address this challenge, we developed integrin αvβ3 targeted microbubbles loaded with IPI549 and indocyanine green, abbreviated as IPI549@αIMBs. This platform enables dual modal ultrasound-fluorescence imaging for monitoring its drug release and distribution, while its combination with ultrasound targeted microbubble destruction(UTMD) technology facilitates the precise delivery and controlled release of IPI549, thereby enhancing synergy with anti-PD1 therapy and improving treatment safety. Our results demonstrate that IPI549@αIMBs effectively targeted to subcutaneous ATC tumors in mice, significantly enhancing IPI549 delivery efficiency. UTMD mediated delivery using IPI549@αIMBs combined with anti-PD1 therapy markedly inhibited subcutaneous ATC tumor growth in mice, effectively reduced the proportion of M2-like tumor associated macrophage, and increased CD8⁺ T cell infiltration, which alleviated the tumor immunosuppressive state. In summary, this study explored a novel therapeutic strategy for ATC, demonstrating the efficacy of the IPI549@αIMB-based UTMD approach combined with anti-PD1 therapy and validating the underlying immunomodulatory mechanisms.

2025-08-01·MOLECULAR DIVERSITY

Enhancing PI3Kγ inhibitor discovery: a machine learning-based virtual screening approach integrating pharmacophores, docking, and molecular descriptors

Article

作者: Yu, Li ; Zhu, Jingyu ; Chen, Yun ; Jin, Jian ; Jia, Lei ; Cai, Yanfei ; Xu, Lei

PI3Kγ is a lipid kinase that is expressed primarily in leukocytes and plays a significant role in tumors, inflammation, and autoimmune diseases. Consequently, considerable attention has been given to the development of pharmacological inhibitors of PI3Kγ. Recently, machine learning-based virtual screening approaches have been increasingly applied in new drug discovery research, potentially providing innovative strategies for the development of PI3Kγ inhibitors. Thus, in this study, we developed a naïve Bayesian classification (NBC) model that integrates molecular descriptors, molecular fingerprints, molecular docking, and pharmacophore models for virtual screening of the PI3Kγ protein. The validation results indicated that the optimal model demonstrated significant potential for differentiating between active and inactive compounds, as well as a reliable ability to identify true PI3Kγ inhibitors with defined biological activity. Additionally, the optimal NBC model provided favorable and unfavorable fragments for PI3Kγ inhibitors, which will help guide the design and discovery of novel PI3Kγ inhibitors. Finally, the optimal NBC model was employed to perform virtual screening on the ChEMBL database, resulting in the identification of several compounds with high potential as PI3Kγ inhibitors. We anticipate that the developed machine learning-based virtual screening approach will offer valuable insights and guidance for the development of novel PI3Kγ inhibitors.

项与 PI3Kγ抑制剂(扬子江药业) 相关的新闻（医药）

2024-05-14

·生物探索

Nature | 罗擎宇等人发现靶向非经典PI3Kγ信号和天然免疫治疗急性白血病

引言磷酸肌醇-3-激酶-γ (PI3Kγ)被认为是肿瘤相关巨噬细胞再极化和促进实体癌抗肿瘤免疫反应的靶标。然而，PI3Kγ在癌细胞中的内在作用尚不清楚。2024年5月8日，哈佛医学院罗擎宇等人在Nature 在线发表题为“Targetable leukaemia dependency on noncanonical PI3Kγ signalling”的研究论文，该研究通过整合无偏倚的全基因组CRISPR干扰筛选和急性白血病的功能分析，定义了高风险亚群(包括髓系、淋巴系和树突状谱系)对PI3Kγ复合物的选择性依赖。这种依赖性的特点是先天炎症信号和磷酸化肌苷激酶调节亚基5 (PIK3R5)的激活，PIK3R5编码PI3Kγ5的调节亚基并稳定活性酶复合物。p21 (RAC1)激活的激酶1 (PAK1)是PI3Kγ的非规范底物，介导这种细胞内在依赖性，并发现通过PI3Kγ抑制PAK1的去磷酸化会损害线粒体氧化磷酸化。选择性PI3Kγ抑制剂eganelisib治疗PIK3R5活化的白血病有效。此外，eganelisib和阿糖胞苷联合使用比单独使用任何一种药物都能延长生存期，即使在基线PIK3R5表达较低的患者源性白血病异种移植物中也是如此，因为阿糖胞苷治疗后的残留白血病细胞具有升高的G蛋白偶联嘌呤能受体活性和PAK1磷酸化。总之，该研究揭示了急性白血病患者对PI3Kγ-PAK1信号的可靶向依赖性，可用于近期评估。尽管最近针对某些急性白血病基因亚群的靶向治疗取得了进展，但许多疾病亚型缺乏机械靶向治疗，大多数患者的长期预后较差。急性髓性白血病(AML)和急性淋巴细胞白血病(ALL)是两种最常见的急性白血病类型。母浆细胞样树突状细胞肿瘤(BPDCN)是一种侵袭性血液系统恶性肿瘤，起源于浆细胞样树突状细胞谱系，与AML和ALL具有相同的临床和病理特征。针对细胞表面表达的CD123的治疗已被批准用于BPDCN，并已在包括AML在内的其他急性白血病中进行了测试，但它并不直接针对细胞内在的致癌途径。研究人员假设BPDCN和其他急性白血病之间的重叠特征可能表明血液系统恶性肿瘤的功能相关亚群具有共同的治疗脆弱性。哺乳动物PI3K家族包含几个类别的多个亚型。I类PI3Ks分为IA类和IB类，产生3-磷酸肌醇脂，激活信号转导途径，II类和III类PI3Ks是内吞膜运输的调节剂。IA类PI3Ks包括三个催化亚基α、β和δ(分别由PIK3CA、PIK3CB和PIK3CD编码)，调控亚基p85α、p55α、p50α、p85β和p55γ(由PIK3R1、PIK3R2和PIK3R3编码)5。IB类PI3K只有一个催化亚基p110γ(由PIK3CG编码)和两个调节亚基p101和p84(分别由PIK3R5和PIK3R6编码)，并通过异源三聚体和小G蛋白被G蛋白偶联受体(GPCRs)激活。几种癌症已经激活了IA类PI3K，许多通路抑制剂已被批准或正在开发中。相比之下，IB类PI3K成分(即酶促p110γ和调节亚基)受到的关注较少，治疗重点仅限于用PI3Kγ抑制剂对巨噬细胞进行重编程，用于实体瘤免疫治疗。PI3Kγ作为细胞内在癌症驱动因子的作用尚不清楚。白血病依赖于非规范PI3Kγ信号（Credit: Nature）该研究发现以先天炎症信号激活的PIK3R5为特征的白血病亚群对PI3Kγ抑制高度敏感。增加的PIK3R5和PIK3CG似乎形成了一个自稳定复合体，能够将PIK3R5的适度转录升高转化为PI3Kγ的实质性激活。出乎意料的是，白血病对PI3Kγ的内在依赖性与传统的PI3K底物AKT4无关，而是依赖于PAK1激酶的磷酸化。PI3Kγ抑制使RAC1失活并降低其与PAK1的相互作用，从而证明PI3Kγ - RAC1 - PAK1信号通路在该白血病亚群中存在。因此，该研究发现PAK1(S144)磷酸化与原发性AML样本中对eganelisib的反应显著相关。几种ATP竞争性和ATP非竞争性PAK变构抑制剂可用，这可能有助于解决这些问题，并提供针对该途径的另一个治疗节点。正如预测的那样，这种组合在PIK3R5升高的模型中发挥协同作用。联合用药对低基线PIK3R5的白血病也有效，可能与G蛋白偶联嘌呤能受体信号传导和糖胞苷持久性白血病细胞中的PAK1磷酸化有关。总之，该研究揭示了急性白血病患者对PI3Kγ-PAK1信号的可靶向依赖性，可用于近期评估。原文链接https://www.nature.com/articles/s41586-024-07410-3责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

临床1期临床2期

2024-05-11

·CPHI制药在线

靶点 | 新希望！白血病治疗迈出关键一步，PI3Kγ抑制剂可能改写AML治疗规则

关注并星标CPHI制药在线图片出自midjourney 2024年5月8日，国际著名科学期刊《自然》杂志发表的一篇论文提出，波士顿的 Dana-Farber 癌症研究所的研究者发现了一种急性白血病治疗的新途径。这一发现可能会影响到髓系和淋巴系白血病的部分患者。其实，研究者这次是发现了白血病治疗的一个新靶点，意义十分重大。因为在制药界有这么一种经典说法：如果说新药是制药业的皇冠，那么新靶点就是制药业皇冠上的明珠。本文对此做一分析。这项研究主要做了些什么？在波士顿的 Dana-Farber 癌症研究所，研究团队的重点是一种叫做 PI3Kγ 的分子复合物。他们发现，某些白血病细胞依赖于 PI3Kγ 复合物的正常运作。这一发现具有重要意义，因为已经有一种药物名为 eganelisib 能够抑制 PI3Kγ 复合物，尽管这种药物最初是为了增强癌症免疫治疗而设计的。研究人员进行了动物实验，发现使用 eganelisib 能够延长白血病动物模型的存活时间。此外，通过分析癌症基因组数据，他们还发现那些对 eganelisib 敏感的患者在现有治疗方法下的生存率较低，这表明这种药物可能对于一些患者来说是一个潜在的重要选择。研究人员还发现，将 eganelisib 与常规的 AML 化疗药物阿糖胞苷联合使用可能会产生协同效应，使患者的存活时间更长。这一联合治疗的机制涉及抑制 PI3Kγ 复合物以及抑制一种称为代谢氧化磷酸化的白血病细胞，后者对于白血病细胞的生长至关重要。简单来说，研究者采用三种不同的白血病模型，分别是BPDCN08、AML11和B-ALL92，来测试这个药物。这些模型都是从真实患者身上取下来的白血病细胞，然后移植到实验室的小白鼠体内建立的。研究结果中显示，通过生存曲线展示了不同治疗组的生存率。例如，对于PIK3R5-high的BPDCN08、AML11和B-ALL92模型，以及PIK3R5-low的BPDCN01、AML20和B-ALL106模型，使用eganelisib和cytarabine联合治疗的小鼠生存期显著长于单独使用任一种药物或对照组。PI3Kγ为何能成为一个潜在的治疗靶点？ PI3Kγ是磷脂酰肌醇-3-激酶-γ的简称，是一种酶类蛋白，参与调节细胞信号转导途径。它在细胞内的功能主要是调控细胞增殖、存活、分化和迁移等生物学过程。在正常生理情况下，PI3Kγ对于细胞的正常功能至关重要。然而，异常激活或过度表达的PI3Kγ与多种疾病的发生和发展密切相关，包括多种类型的癌症。在白血病的研究中，PI3Kγ被发现在癌症微环境中扮演了重要角色。具体来说，它通过影响肿瘤相关巨噬细胞来促进抗肿瘤免疫反应。同时，在高危白血病患者中，白血病细胞对PI3Kγ复合体的依赖性增强。这表明PI3Kγ在白血病发展过程中可能扮演了关键角色。因此，针对PI3Kγ的治疗策略被视为一种潜在的治疗途径。通过使用PI3Kγ抑制剂，如eganelisib，可以抑制PI3Kγ的活性，从而干扰白血病细胞的生存和增殖。与传统的化疗药物联合使用，如与阿糖胞苷联合使用，可能产生更好的治疗效果，延长患者的生存期。总之，这项研究为白血病治疗带来了新的转机，也突显了PI3Kγ可以作为一个潜在的治疗靶点，可以改善白血病的疗效。图片出自midjourney 新靶点为白血病患者提供了更多治疗选择这项研究的重要性体现在以下五个方面：首先，通过发现磷脂酰肌醇-3-激酶-γ（PI3Kγ）在白血病中的非经典作用，开辟了新的治疗途径，为白血病患者提供了更多治疗选择。其次，使用PI3Kγ抑制剂eganelisib单独或与化疗药物联合治疗，显著提高了患者的生存期，增强了治疗效果外，还可以深入了解PI3Kγ在肿瘤微环境中的作用，有助于拓展对癌症发展机制的认识，为个体化治疗提供了新思路。最重要的是，发现依赖PI3Kγ的白血病亚群，有助于实现更精准的治疗，减少药物毒副作用，提高患者的治疗效果。最后，这项研究对于改善白血病患者的治疗前景和生存率具有重要意义。小结综上所述，当科学家发现新的药物靶点时，就像在制药业的皇冠上添加了一颗珍贵的明珠，为研发更有效、更精准的药物提供了新的方向和机会。因此，新的药物靶点在推动医学科学进步，为患者提供更多治疗选择方面扮演着非常重要的角色，为医疗带来了希望和福祉。当前这一发现为那些骨髓性白血病患者带来了新的希望，而这个希望可能很快就会成为现实。目前，研究团队正在努力设计临床试验，以验证这些发现，并将它们应用于患者身上。参考资料：Luo, Q., Raulston, E.G., Prado, M.A. et al. Targetable leukaemia dependency on noncanonical PI3Kγ signalling. Nature (2024). https://doi.org/10.1038/s41586-024-07410-3【智药研习社近期线下课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床结果

2023-07-26

·FierceBiotech

Infinity lays off 78% of staff, 3 board members after MEI merger fails

Infinity is considering whether to withdraw its appeal for Nasdaq not to delist the company. With hopes of a merger with MEI Pharma now sunk for good, Infinity Pharmaceuticals is jettisoning three-quarters of its staff and three board members to stay afloat while it scans the horizon for another financial life raft. The planned combination of MEI Pharma and Infinity had been in the works since February. Yet despite surviving the intervention of a surprise bidder at the last minute, MEI’s shareholders finally voted on the proposal on Sunday and scuppered the deal for good. Infinity had made clear the stakes from the start, warning in March that the proposed combination with MEI could be the last chance to avoid bankruptcy as its lead clinical candidate eganelisib eats up remaining cash reserves. In a post-market release Tuesday, Infinity said it continues to believe that eganelisib “offers a near-term value creation opportunity that would be attractive to potential third-party acquirers.” The biotech has already taken the PI3Kγ inhibitor up to the initiation of a planned global phase 2 trial in head and neck squamous cell carcinoma but needs another company to take the candidate over the line. In order to keep going while Infinity seeks a “strategic transaction to maximize eganelisib’s potential,” the biotech is laying off 21 employees—equivalent to 78% of its current workforce. Following their colleagues out the door will be three of the company’s eight board members. “The remaining five members of the board have agreed to serve without compensation for the remainder of their board service,” Infinity explained. If that wasn’t enough of a sign of the dire financial straits the company is now in, Infinity is also considering whether to withdraw an appeal for Nasdaq not to delist the company from the exchange. The biotech’s share price sunk below $1—the minimum required to remain on the Nasdaq—in November 2022 and has never resurfaced. Infinity ended 2022 with $38.3 million in cash and equivalents, a sizable drop on the $80.7 million in the bank at the start of the year. Back in March 2023, the company explained that failing to get the MEI deal over the line meant the cash runway would run out in the second half of this year as opposed to its previous timeline of 2024. “This shorter cash runway is a result of expenditures related to merger activities and the advancement of eganelisib,” the company said at the time.

高管变更临床2期IPO

100 项与 PI3Kγ抑制剂(扬子江药业) 相关的药物交易

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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
炎症	临床前	中国	扬子江药业集团有限公司	2024-03-07
代谢性疾病	临床前	中国	扬子江药业集团有限公司	2024-03-07
肿瘤	临床前	中国	扬子江药业集团有限公司	2024-03-07