A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination With Intensive Induction and Consolidation Chemotherapy in Adults With Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia

The primary objective of this study is to evaluate the efficacy of entospletinib (ENTO) compared to placebo when added to chemotherapy in previously untreated nucleophosmin-1 mutated (NPM1-m) acute myeloid leukemia (AML), as defined by the rate of molecularly defined measurable residual disease (MRD).

开始日期2021-11-24

申办/合作机构

Kronos Bio, Inc.

NCT03225924

/ Terminated临床1/2期IIT

Phase Ib - II Study of Entospletinib (ENTO) in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) Patients With aaIPI>=1 Treated by Rituximab, Cyclophosphamide, Hydroxydaunomycin, Oncovin, and Prednisone (R-CHOP)

The primary objective of the phase Ib of the study is to determine the recommended phase 2 dose (RP2D) for entospletinib (ENTO) in patients treated with R-CHOP.
The primary objective of the phase II is to determine the complete metabolic response (CMR) rate by the Lugano classification 2014 (Deauville scale 1-3) at the end of treatment.

开始日期2017-07-26

申办/合作机构

Le LYSARC

NCT03010358

/ Completed临床1/2期

A Phase I/II Study of Syk Inhibitor Entospletinib (GS-9973) in Combination With Obinutuzumab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and B-Cell Malignancies

This phase I/II trial studies the side effect and best dose of entospletinib when giving together with obinutuzumab and to see how well they work in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that has come back. Entospletinib may stop the growth of cancer cells by blocking some of the enzymes need for cell growth. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. Giving entospletinib and obinutuzumab together may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma.

开始日期2017-07-17

申办/合作机构

Gilead Sciences, Inc.

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100 项与 Entospletinib Dimesylate 相关的临床结果

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100 项与 Entospletinib Dimesylate 相关的转化医学

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100 项与 Entospletinib Dimesylate 相关的专利（医药）

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项与 Entospletinib Dimesylate 相关的文献（医药）

2025-03-01·HEMATOLOGICAL ONCOLOGY

Gene Expression Profiling in Acute Myeloid Leukemia Patient Subgroups With High and Low Sensitivity Toward SYK Inhibitors

Article

作者: Brattås, Marte Karen ; Rye, Kristin Paulsen ; Johansen, Silje ; Reikvam, Håkon ; Hatfield, Kimberley Joanne ; Görtler, Franziska

ABSTRACT:

Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the uncontrolled proliferation of myeloid cells, and despite recent treatment advances, patient outcomes remain suboptimal. The cytoplasmic spleen tyrosine kinase (SYK) has emerged as a promising therapeutic target in AML due to its role in promoting leukemic cell survival, proliferation, and chemoresistance. This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK‐659, and RO9021. Our findings revealed significant heterogeneity among patients, leading to the identification of two distinct patient sample groups that were identified as having either high or low sensitivity toward SYK inhibitors. Furthermore, gene expression profiling through RNA sequencing of AML patient samples uncovered 97 significantly differentially expressed genes (DEGs) between the two patient groups with high or low in vitro sensitivity toward SYK inhibitors. Pathway enrichment analyses revealed that the high‐sensitivity group was enriched in biological processes related to positive gene regulation and significant pathways included cell adhesion molecules and proteoglycans. In contrast, the low‐sensitivity group showed enrichment in pathways related to PI3K‐Akt signaling and JAK‐STAT signaling.Gene set enrichment analysis further highlighted that high‐sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low‐sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML.

2024-10-01·Environmental toxicology

Exploring the impact of ITGB2 on glioma progression and treatment: Insights from non‐apoptotic cell death and immunotherapy

Article

作者: Chen, Zigui ; Hu, Linwang ; Liu, Chao ; Zhuang, Junhong ; Peng, Jun ; Miao, Changfeng ; Xia, Ying ; Zeng, Biying

Abstract:

In the realm of glioma treatment, our groundbreaking research has uncovered the pivotal role of Integrin Beta 2 (ITGB2) in non‐apoptotic cell death and its profound implications for immunotherapy efficacy. Gliomas, known for their aggressive and infiltrative nature, demand innovative therapeutic strategies for improved patient outcomes. Our study bridges a critical gap by examining the interplay between non‐apoptotic cell death and immunotherapy response in gliomas. Through comprehensive analysis of ten diverse glioma datasets, we developed a unique death enrichment score and identified ITGB2 as a significant risk marker. This study demonstrates that ITGB2 can predict immune activity, mutation characteristics, and drug response in glioma patients. We reveal that ITGB2 not only mediates glioma proliferation and migration but also crucially influences immunotherapy responses by modulating the interaction between gliomas and macrophages by single‐cell sequencing analysis (iTalk and ICELLNET). Employing a variety of molecular and cellular methodologies, including in vitro models, our findings highlight ITGB2 as a potent marker in glioma biology, particularly impacting macrophage migration and polarization. We present compelling evidence of ITGB2's dual role in regulating tumor cell behavior and shaping the immune landscape, thereby influencing therapeutic outcomes. The study underlines the potential of ITGB2‐targeted strategies in enhancing the efficacy of immunotherapy and opens new avenues for personalized treatment approaches in glioma management. In conclusion, this research marks a significant stride in understanding glioma pathology and therapy, positioning ITGB2 as a key biomarker and a promising target in the quest for effective glioma treatments.

2024-09-01·CARDIOVASCULAR PATHOLOGY

A pathological study on the efficacy of Syk inhibitors in a Candida albicans-induced aortic root vasculitis murine model

Article

作者: Asakawa, Nanae ; Miura, Noriko ; Yokouchi, Yuki ; Oharaseki, Toshiaki ; Takahashi, Kei ; Ohno, Naohito

BACKGROUND:

The activation of innate immunity may be involved in the development of Candida albicans-induced murine vasculitis, which resembles Kawasaki disease (KD) vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis.

METHODS AND RESULTS:

DBA/2 male mice were intraperitoneally injected with a vasculitis-inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors.

CONCLUSION:

Candida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis.

项与 Entospletinib Dimesylate 相关的新闻（医药）

2025-05-01

·GlobeNewswire-Health Care

Kronos Bio Enters into Agreement to Be Acquired by Concentra Biosciences for $0.57 in Cash per Share Plus a Contingent Value Right

CAMBRIDGE, Mass., May 01, 2025 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. ("Kronos Bio") (Nasdaq: KRON), a biotechnology company that has been developing small molecule therapeutics to address cancers and other diseases driven by deregulated transcription, today announced that it has entered into a definitive merger agreement (the “Merger Agreement”) with Concentra Biosciences, LLC ( “Concentra”), whereby Concentra will acquire Kronos Bio for $0.57 in cash per share of Kronos Bio common stock (“Kronos Bio Common Stock”), plus one non-tradeable contingent value right ("CVR"), which represents the right to receive: (i) 50% of the net proceeds in the case of a disposition of the Company’s product candidates known as KB-9558 and KB-7898 that occurs within 2 years following closing; (ii) 100% of the net proceeds in the case of a disposition of the Company’s product candidates known as KB-0742, lanraplenib and entospletinib that occurs prior to closing; (iii) 100% of cost savings realized prior to closing; (iv) 80% of cost savings realized between the merger closing date and the second (2nd) anniversary of the merger closing date; and (v) 50% of cost savings realized between the second (2nd) anniversary of the merger closing date and the third (3rd) anniversary of the merger closing date, each pursuant to the contingent value rights agreement (the “CVR Agreement”). Following a review process conducted with the assistance of its legal and financial advisors, the Kronos Bio Board of Directors has determined that the acquisition by Concentra is in the best interests of all Kronos Bio shareholders and has approved the Merger Agreement and related transactions. Pursuant and subject to the terms of the Merger Agreement, a wholly owned subsidiary of Concentra will commence a tender offer (the “Offer”) by May 15, 2025 to acquire all outstanding shares of Kronos Bio Common Stock. Closing of the Offer is subject to certain conditions, including the tender of Kronos Bio Common Stock representing at least a majority of the total number of outstanding shares (including any shares held by Concentra), the availability of at least $40.0 million of cash (net of transaction costs and other liabilities) at closing, and other customary closing conditions. Kronos Bio officers, directors and their respective affiliates holding approximately 27% of Kronos Bio Common Stock have signed tender and support agreements under which such parties have agreed to tender their shares in the Offer and support the merger transaction. The merger transaction is expected to close mid-2025. About Kronos BioKronos Bio is a biopharmaceutical company that has historically focused on the discovery and development of small molecule therapeutics to address deregulated transcription, a hallmark of cancer and autoimmune diseases. Kronos Bio has a research facility in Cambridge, Mass. For more information, visit https://www.kronosbio.com. AdvisorsGoodwin Procter LLP is acting as legal counsel to Kronos Bio and Leerink Partners is acting as sole financial advisor to Kronos Bio. Gibson, Dunn & Crutcher LLP is acting as legal counsel to Concentra. Forward-Looking Statements This release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Kronos Bio’s beliefs and expectations and statements about the Offer, merger, related transactions contemplated by the Merger Agreement and the CVR Agreement (the “Transactions”), including the timing of and closing conditions to the Transactions, and the potential effects of the proposed Transactions on Kronos Bio and the potential payment of proceeds to the Kronos Bio stockholders, if any, pursuant to the CVR Agreement. These statements may be identified by their use of forward-looking terminology including, but not limited to, “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” and “would,” and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance and involve risks and uncertainties that could cause actual results to differ materially from those projected, expressed or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the possibility that various closing conditions set forth in the Merger Agreement may not be satisfied or waived, including uncertainties as to the percentage of Kronos Bio’s stockholders tendering their shares in the Offer; the possibility that competing offers will be made; the risk that the Transactions may not be completed in a timely manner, or at all, which may adversely affect Kronos Bio’s business and the price of its common stock; costs associated with the proposed Transactions; the risk that any stockholder litigation in connection with the Transactions may result in significant costs of defense, indemnification and liability; the risk that activities related to the CVR Agreement may not result in any value to the Kronos Bio stockholders; and other risks and uncertainties discussed in Kronos Bio’s most recent annual report filed with the Securities and Exchange Commission (the “SEC”) as well as in Kronos Bio’s subsequent filings with the SEC. As a result of such risks and uncertainties, Kronos Bio’s actual results may differ materially from any future results, performance or achievements discussed in or implied by the forward-looking statements contained herein. There can be no assurance that the proposed Transactions will in fact be consummated. Kronos Bio cautions investors not to unduly rely on any forward-looking statements. The forward-looking statements contained in this release are made as of the date hereof, and Kronos Bio undertakes no obligation to update any forward-looking statements, whether as a result of future events, new information or otherwise, except as expressly required by law. All forward-looking statements in this document are qualified in their entirety by this cautionary statement. Additional Information and Where to Find It The Offer described in this release has not yet commenced, and this release is neither a recommendation, nor an offer to purchase nor a solicitation of an offer to sell any shares of the common stock of Kronos Bio or any other securities. On the commencement date of the Offer, a tender offer statement on Schedule TO, including an offer to purchase, a letter of transmittal and related documents, will be filed with the SEC by Concentra and its acquisition subsidiary, and a Solicitation/Recommendation Statement on Schedule 14D-9 will be filed with the SEC by Kronos Bio. The Offer to purchase the outstanding shares of the common stock of Kronos Bio will only be made pursuant to the offer to purchase, the letter of transmittal and related documents filed as a part of the Schedule TO. INVESTORS AND SECURITY HOLDERS ARE URGED TO READ THE TENDER OFFER MATERIALS (INCLUDING THE OFFER TO PURCHASE, A LETTER OF TRANSMITTAL AND RELATED DOCUMENTS) AND THE SOLICITATION/RECOMMENDATION STATEMENT ON SCHEDULE 14D-9 REGARDING THE OFFER, AS THEY MAY BE AMENDED OR SUPPLEMENTED FROM TIME TO TIME, WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION THAT INVESTORS AND SECURITY HOLDERS SHOULD CONSIDER BEFORE MAKING ANY DECISION REGARDING TENDERING THEIR SHARES, INCLUDING THE TERMS AND CONDITIONS OF THE OFFER. Investors and security holders may obtain a free copy of these statements (when available) and other documents filed with the SEC at the website maintained by the SEC at www.sec.gov or by directing such requests to the information agent for the Offer, which will be named in the tender offer statement. Investors and security holders may also obtain, at no charge, the documents filed or furnished to the SEC by Kronos Bio under the “Investors & Media” section of Kronos Bio’s website at https://ir.kronosbio.com/financials-filings/sec-filings. Contact Information: Investors: Denise Powell denise@redhousecomms.com Media: Kelli Perkins kelli@redhousecomms.com

并购

2024-09-04

·和黄医药官微

活动回顾 | 和黄医药免疫性血小板减少症专家分享会

近日，和黄医药通过线上直播的形式举办了一场面向投资者的医师专家分享会，邀请一位免疫性血小板减少症（ITP）领域的教授及意见领袖讨论免疫性血小板减少症的治疗前景。 - 以下是投资者与ITP专家的精彩问答节录 - Q 国内ITP的流行病学现状如何？患者人数大约是多少？ “ 我刚看完今天的门诊，差不多看了60个病人，其中ITP患者约占一半。在流行病学层面，很遗憾从上世纪90年代至今，都没有中国人自己的流行病数据，通常引用的是海外的每年2/100,000到4/100,000的发病率。这个数据对比我在实际临床中看到的病人数还是偏低的，因为ITP患者数量在我门诊中占了很大比例。整体来看， ITP是血液系统最常见的出血性疾病，发病率甚至超过了白血病和再生障碍性贫血。 Q ITP的诊断标准是什么? “ 目前国内采用的是2020年制定的专家共识。通常情况下，连续两次检测血小板低于30×109/L（3万/μL），并且没有形态学异常，可以初步诊断为ITP。关键是排除其他继发性疾病，如结缔组织病、感染等。此外，特异性实验室检查也在推广中，我们中心也处理了许多来自全国的血小板糖蛋白特异性自身抗体样本。除了血小板破坏增加，生成不足也是ITP的重要机制，TPO（血小板生成素）的检测因此变得越来越重要。 Q 目前ITP的治疗现状如？一线、二线和三线的治疗方案是什么？ “ 一线用得最多的还是激素，如短效的泼尼松，中效的地塞米松。丙球由于价格较高，主要用于紧急治疗。二线治疗药物选择相对丰富，中国在这方面走在世界前列，涵盖了重组TPO药物、TPO受体激动剂（如艾曲泊帕）、CD20单抗等联合治疗方案。二线治疗在实际临床中占很大比例。对于经过二线治疗效果不佳的患者，三线治疗多采用免疫抑制剂，如环孢素、硫唑嘌呤等，它们的作用机制不一样，但主要问题是毒性比较大，副作用比较大，所以患者难以长期使用。整体来讲，大家现在ITP的治疗原则，这也是中国和国际一个接轨，我们国内很多过去看病只讲指标的变化，不注重患者的生活质量，但是现在的话，也越来越关注生活质量。 Q 如何解读和黄医药索乐匹尼布ESLIM-01研究？ “ 和黄医药我觉得还是非常厉害，筛选和比较之后找到了这个分子。它的IC50值只有0.025，而R406（福他替尼）是0.054，差不多少了一倍以上的水平。与其他SYK抑制剂如GS9973相比，索乐匹尼布的抑制活性更高。整体来看水平高一些，是一个很好的药理学发现。我们随后开展了ITP的关键性注册研究，入组患者数量有188例，这对于ITP而言是一个比较大的样本量。这些患者的ITP病程较长（12个月），且均接受过标准治疗，研究的挑战性较高。实际接临床试验之前，我其实并不是很有信心，因为之前大家都很看好的福他替尼，做出来的数据不理想。索乐匹尼布结果出来我就感到很欣喜，其持续应答率接近50%，表明患者有可能停药，且疗效稳定持久。另外最值得一提的是，针对既往接受过TPO/TPO-RA治疗的患者，索乐匹尼布的有效率高达75%，显示出巨大潜力。我还申请开展了IIT研究。当前，TPO类药物在国内普及迅速，但仍有2/3的患者在治疗后复发，75%的有效率对解决这一问题至关重要。索乐匹尼布的快速起效也是其优势之一，通常在一周内显效，相较于海曲泊帕、艾曲泊帕等药物的14天起效时间更具优势。 Q 从临床角度来讲，临床研究的终点包括很多，如总缓解率，持续缓解率，以及血小板变化曲线，您认为哪个治疗指标最重要？ “ 设立多个研究终点是因为每个终点都有其临床意义，但是主要终点，我们认为是最具有临床意义的。虽然泊帕类药物和福他替尼总体应答率可以达到70%以上，但持续应答才是真正的挑战。不同药物在持续应答率和稳定性方面存在差异，因此我们将持续应答率作为最关键的研究终点，认为这是衡量药物疗效的最重要指标。 Q 对于患者依从性，口服小分子药物和每周一次的皮下注射，哪个更有优势？ “ 在2019年ASH会议上，医生与患者共同讨论了用药方案，最终的指南建议根据患者的生活安排进行平衡评估。这与患者的个人意愿密切相关。因此，我们通常会与患者讨论这个问题，询问他们是希望每周注射一次以延长药效，还是每天口服药物。目前来看，中国患者更倾向于每天口服药物。 Q 您提到SYK在机制上可能更具优势，除了B细胞外，还可能对巨噬细胞等免疫细胞起作用。您认为多维度的免疫细胞调控在ITP治疗中更为重要吗？从MOA上看，如何比较BTK和SYK抑制剂？ “ ITP的诊疗难度甚至超过白血病，其发病机制更加复杂。因此，多靶点、多途径的治疗可能效果更好。从我们现有的经验来看，SYK抑制剂的效果确实更好。总体来看，SYK与BTK抑制剂之间确实存在差异。从机制上看，虽然BTK和SYK都是激酶，但SYK表达的细胞类型更为广泛，因此在临床应用中，SYK抑制剂可能更具优势。 Q 对于主要终点的设定，尤其是持续应答率，在不同临床试验中的定义有所不同。有的每两周随访一次，达到六周中四次应答；有的每周随访一次，达到八周中六次应答。哪种设定更为严格？ “ 一般来说，随访周期越长，研究的严谨性和水平就越高。比如随访两个月每周一次，不如随访半年，这样能够更准确地评估药物的持续疗效，研究的严格性也会更高。 Q ITP作为一种良性疾病，是否对患者影响较小？ “ 虽然ITP被认为是一种良性疾病，但其对患者的影响仍然非常大。长期血小板水平在10×109/L至20×109/L，仅为正常值的1/5或更低，这让患者感到极度不安，每天生活在紧张状态中。虽然肿瘤恶性较高，但并不总是立即威胁生命。相比之下，ITP虽然是良性疾病，但如果血小板降至1万/μL以下，可能引发严重出血，如消化道、子宫或颅内出血，这些都是致命性出血。尤其对于60岁以上的老年人，出血风险比年轻人高出5倍。尽管ITP不是恶性肿瘤，但其生命危险更为直接，类似于心血管疾病，未来也可能发展为一种慢性疾病，因此需要重视其防治。此外，ITP严重影响患者的生活质量和心理健康。频繁输血不仅增加了患者的压力，也对血液资源造成了巨大影响，且输血效果往往不理想。这些都是ITP带来的重大问题。和黄医药（纳斯达克/伦敦证交所：HCM；香港交易所：13）是一家处于商业化阶段的创新型生物医药公司，致力于发现、全球开发和商业化治疗癌症和免疫性疾病的靶向药物和免疫疗法。集团旗下公司共有约5,000名员工，其中核心的肿瘤/免疫业务拥有约1,800人的团队。自成立以来，和黄医药致力于将自主发现的候选药物带向全球患者，首三个药物已在中国上市，其中首个药物亦于美国和欧洲上市。欲了解更多详情，请访问：www.hutch-med.com/sc 。

临床研究

2024-03-20

·精准药物

氧杂环丁烷在药物发现中的应用

1背景当前药物化学项目集中于更多更具挑战性的生物靶点，候选药物的分子复杂性大大增加。为此，药物研究者们不断寻找创新的功能分子基团以应对这一挑战。今天我们要分享的是伦敦帝国理工学院化学系分子科学研究中心发表在Journal of Medicinal Chemistry上的文章：Oxetanes in Drug Discovery Campaigns。文章介绍了氧杂环丁烷在药物发现中的应用以及应用中的一些优缺点。四元杂环因其具有低分子量，高极性和特异的三维属性而深受研究者们的欢迎，其中氧杂环丁烷基团被报道的更多（图1）。图1. (a) 具有生物活性的四元杂环的例子；（b）文献中报道四元杂环的数量变化氧杂环丁烷基团在天然产物中常有出现，最著名的有FDA批准的紫杉醇（图2a），虽然氧杂环丁烷被证明不是紫杉醇生物活性的必要结构，但含氧杂环丁烷基团的类似物的亲和力和细胞毒性低于紫杉醇的母体结构。图2. (a) 紫杉醇；(b) gem-二甲基和羰基衍生物的等排体 3,3-二取代的氧杂环丁烷可以作为gem-二甲基和羰基的等排体（图2b），Carreira 团队和罗氏公司合作证明氧杂环丁烷可以作为gem-二甲基的等排体来阻断候选药物中C-H活性位点的代谢 [1]；氧杂环丁烷还可以作为羰基的等排体用来改善药物分子的代谢稳定性及提高药物分子的水溶性等性质。2应用举例氧杂环丁烷在专利和学术期刊中广泛出现，目前有七种包含氧杂环丁烷的候选药物正在进行临床试验（图3a-3g）。七种候选药物中有超过50%的结构是氨基-氧杂环丁烷，其中氧杂环丁烷基团可以减弱氨基的碱度。此外，七种化合物中有6种化合物的氧杂环丁烷是3位取代，因为3位取代的稳定性和可合成性更高。通常在药物设计的后期引入氧杂环丁烷来改善先导化合物的PK性质（logD、溶解度、清除率或碱度等）。图3a. Crenolanib[2] 图3b. Fenebrutinib[3]图3b Fenebrutinib中氧杂环丁烷的引入降低了化合物4的pKaH，对化合物的溶解度和药代动力学特性也有一定的益处。图3c. Ziresovir[4]图3c 中Ziresovir，在研发后期通过引入氧杂环丁烷来降低化合物5中氨基的碱度，氧杂环丁烷小体积的特性也有助于降低分布体积，避免药物在组织中堆积，降低了毒性风险。图3d. Lanraplenib[5]图3d 中Entospletinib 由于其不充分的溶解度，与质子泵抑制剂不良的相互作用以及吗啉环氧化导致的高代谢清除率退出了临床开发。在后期优化阶段引入4-乙基哌嗪替换吗啉改善了化合物的代谢稳定性，随后引入氧杂环丁烷替代乙基，降低了化合物的碱度，提高了在 pH 2 和 Caco-2 渗透性下的溶解度。图3e. Danuglipron[6]图3e Danuglipron 中氧杂环丁烷作为一个小的极性头被引入，它增加了化合物的活性，没有对 LogD 和其他物理化学性质（如清除率和毒性）产生负面影响。图3f. GDC-0349[7]图3f 化合物7有较差的游离血浆清除率和避免由细胞色素P450酶类（CYP酶）时间依赖性抑制（TDl），这可能导致药物存在潜在的毒性问题。将嘧啶环换成烷基确实将CYP抑制降低了10倍以上，但心脏毒性增高（hERG：IC50= 8.5 μM），这与叔烷基胺碱度增加有关（pKaH= 7.6）。GDC-0349 在氮上引入氧杂环丁烷取代基降低了pKaH，同时降低了hERG毒性，与化合物7相比，游离血浆清除率也降低了10倍。图3g. PF-06821497[8]图3g中先导化合物8是一种有效的EZH2抑制剂，但代谢稳定性差且溶解度不足。可通过降低LogD和增加立体性来改善这两种特性。最后化合物9引入了甲氧基和氧杂环丁烷，显著改善了代谢和溶解度特性，并使化合物更适合蛋白口袋。图4. 化合物PF-06821497与EZH2的共晶体结构新引入的氧杂环丁烷立体中心对结合很重要，化合物PF-06821497与 EZH2 复合物的共晶结构表明（图4），氧杂环丁烷取代基在蛋白空腔中占据了一个确定的空间，氧杂环丁烷中的CH 基团和两个酪氨酸侧链之间存在两个潜在的 CH−π相互作用。3小结氧杂环丁烷基团在药物发现中有非常重要的应用，研究表明，氧杂环丁烷的稳定性与其取代模式密切相关，其中3,3-二取代最稳定。研究者们揭示了氧杂环丁烷在药物研发中的许多潜在优势，但也发现了很多的挑战。氧杂环丁烷的潜在优势1.氧杂环丁烷的诱导吸电子效应可以降低相邻基团的pKaH （α位降低约2.7、β位降低约1.9、γ位降低约0.7、δ位降低约0.3），可通过引入氧杂环丁烷来减少或消除药物化合物的碱性。2.氧杂环丁烷中sp3杂化的碳原子增加了化合物的立体性，这种构象效应可以增加化合物的水溶性。3.氧杂环丁烷的体积小，极性大，可用于阻断代谢不稳定的位点，并且不会显著增加化合物的分子量和亲脂性。4.氧杂环丁烷可以作为羰基官能团的生物等排体，这可能有助于规避羰基特异性酶降解，提高水溶性，获得新的IP空间。5.氧杂环丁烷适度的环应变可以引导通过活性药物成分（APIs）代谢而被微粒体环氧化物水解酶（mEH）降解，从而避免由CYP酶清除导致的肝毒性。氧杂环丁烷的潜在劣势，面临的挑战及未来的方向1.氧杂环丁烷的合成仍然具有挑战性。2.氧杂环丁烷构建模块的选择是有限的，这种约束影响了药物化合物中氧杂环丁烷结构的取代模式。3.氧杂环丁烷在酸性条件或高温条件下是不稳定的，所以预测给定的氧杂环丁烷取代模式的稳定性是具有挑战性的。4.氧杂环丁烷在严苛条件下的潜在不稳定性可能成为多步大规模合成的问题，所以通常氧杂环丁烷仅在药物开发的最后阶段引入，以补救一些有问题的物理化学性质，如溶解度或代谢稳定性。5.氧杂环丁烷化合物相关性质的数据集有限，限制了基于数据的预测。参考文献（上下滑动可查看更多）本文：Rojas, J. Oxetanes in Drug Discovery Campaigns. J. Med. Chem. 2023, 66, 12697–12709.[1]. Wuitschik, G.; etal. Oxetanes as Promising Modules in Drug Discovery. Angew. Chem., Int. Ed. 2006, 45, 7736−7739.[2]. Smith, C. C.; etal. Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 5319−5324.[3]. Crawford, J. J.; Zhang, H. In ACS Symposium Series; American Chemical Society, 2019; Vol. 1332, pp 239−266.[4]. Zheng, X.; etal. Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors. J. Med. Chem. 2018, 61, 10228−10241.[5]. Blomgren, P.; etal. Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases. ACS Med. Chem. Lett. 2020, 11, 506−513.[6]. Griffith, D. A.; etal. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. J. Med. Chem. 2022, 65, 8208−8226.[7]. Pei, Z.; etal. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349. ACS Med. Chem. Lett. 2013, 4, 103−107.[8]. Kung, P.-P.; etal. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(Methoxy(Oxetan-3-yl)Methyl)-2-((4- Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihy-droisoquinolin-1(2H)-one (PF-06821497). J. Med. Chem. 2018, 61, 650−665.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↓

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100 项与 Entospletinib Dimesylate 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
NPM1突变急性髓系白血病	临床3期	美国	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	巴西	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	加拿大	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	捷克	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	法国	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	德国	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	匈牙利	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	以色列	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	意大利	Kronos Bio, Inc.	2021-11-24
NPM1突变急性髓系白血病	临床3期	波兰	Kronos Bio, Inc.	2021-11-24

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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


NCT05020665 (CTgov)	临床3期	NPM1突变急性髓系白血病	15	anthracycline+ENTO+cytarabine (ENTO)	鑰鹽鏇廠願膚製糧憲蓋 = 餘製製顧簾選製餘淵遞鏇膚鏇糧蓋鹽醖膚襯窪 (鏇網餘範繭餘膚繭憲範, 壓鑰願鏇鹹繭鑰鏇鹽鹹 ~ 鏇夢夢鏇顧膚糧選網範) 更多	-	2024-01-10
				placebo+cytarabine (Placebo)	鑰鹽鏇廠願膚製糧憲蓋 = 範醖網鬱觸遞衊鏇齋積鏇膚鏇糧蓋鹽醖膚襯窪 (鏇網餘範繭餘膚繭憲範, 獵鏇鑰鬱簾餘膚窪獵夢 ~ 衊獵簾顧製齋襯鏇製願) 更多
NCT03010358 (CTgov)	临床1/2期	淋巴浆细胞性淋巴瘤 \| 贫血 \| 滤泡性淋巴瘤 ... 更多	24	obinutuzumab+entospletinib (Phase 1, Dose 1-2)	壓醖鹹糧憲衊齋鹽鏇膚 = 鏇網夢選製鹹築獵艱夢選鏇鹽獵構餘築廠願壓 (鏇顧憲淵窪廠網衊鬱淵, 襯鬱齋積願構醖範築艱 ~ 選選範積獵廠範醖網餘)	-	2023-08-08
				obinutuzumab+entospletinib (All Research Participants)	壓顧窪艱簾獵餘齋顧壓 = 膚簾糧積鑰膚獵網鬱鏇遞醖壓廠夢餘簾製觸選 (選膚憲壓餘窪蓋醖糧選, 蓋網鏇夢蓋鑰範築醖獵 ~ 網願窪膚鏇構醖鹽蓋艱) 更多
NCT03010358 (ASH 12021 \| ASH 22021) 人工标引	临床1/2期	复发性慢性淋巴细胞白血病	24	Entospletinib+Obinutuzumab	衊範網構築鑰齋襯糧夢(壓齋窪廠獵齋廠積積淵) = entospletinib 400 mg twice-daily 願襯鑰積範艱築壓鑰鹽 (夢遞遞襯構獵艱憲製繭 )	积极	2021-11-05
NCT02457598 (Pubmed \| Clin Cancer Res)	临床1期	慢性淋巴细胞白血病	53	Tirabrutinib monotherapy	衊構艱淵齋遞壓憲網艱(獵襯廠積鏇築憲廠壓襯) = 襯鬱簾蓋鏇簾廠範觸憲鑰憲積鹹衊繭製廠壓構 (鑰製鏇積願艱糧膚構築 ) 更多	-	2020-06-15
				Tirabrutinib + Idelalisib	衊構艱淵齋遞壓憲網艱(獵襯廠積鏇築憲廠壓襯) = 醖獵齋窪膚齋範艱鏇繭鑰憲積鹹衊繭製廠壓構 (鑰製鏇積願艱糧膚構築 ) 更多
NCT01796470 (CTgov)	临床2期	套细胞淋巴瘤 \| 慢性淋巴细胞白血病 \| 弥漫性大B细胞淋巴瘤 ... 更多	66	Idelalisib+Entospletinib (Entospletinib + Idelalisib CLL)	鹽築廠淵蓋齋網製窪醖 = 齋淵齋衊窪構選積衊膚襯範廠鹽選網繭夢構鬱 (壓鹹鑰鹹憲餘夢餘蓋壓, 鏇築艱膚願鹽膚構餘願 ~ 淵襯窪獵遞蓋積窪餘選) 更多	-	2020-06-02
				Idelalisib iNHL+Entospletinib (Entospletinib + Idelalisib iNHL: FL)	鹽築廠淵蓋齋網製窪醖 = 積構鏇選鑰觸衊醖鑰遞襯範廠鹽選網繭夢構鬱 (壓鹹鑰鹹憲餘夢餘蓋壓, 鏇鏇簾選衊蓋網簾製衊 ~ 構醖壓願窪網醖壓網鬱) 更多
NCT03135028 (Japanese AML, CTgov)	临床1期	急性髓性白血病	9	ENTO	夢憲淵獵範積艱鬱製範 = 襯鏇廠衊衊鬱鹹顧鏇壓積鹽艱鹽遞獵願糧齋鹹 (鑰鹹衊鏇淵網膚齋鹹鹽, 簾鬱遞範鹽觸遞淵醖鬱 ~ 繭製觸窪醖壓鬱鑰夢齋) 更多	-	2020-03-06
NCT02983617 (CTgov)	临床2期	慢性淋巴细胞白血病	36	Tirabrutinib+Entospletinib (Tirabrutinib + Entospletinib)	遞齋齋醖積積簾襯壓窪 = 築鬱壓齋簾選窪糧鬱鏇夢鑰餘蓋襯鹽淵選獵齋 (窪鹹積願醖鬱製襯糧願, 襯範製襯壓製鏇獵膚餘 ~ 窪製醖鏇範醖憲網夢淵) 更多	-	2020-02-28
				Obinutuzumab+Tirabrutinib+Entospletinib (Tirabrutinib + Entospletinib + Obinutuzumab)	遞齋齋醖積積簾襯壓窪 = 鏇遞獵選網獵夢糧醖醖夢鑰餘蓋襯鹽淵選獵齋 (窪鹹積願醖鬱製襯糧願, 襯窪觸鑰憲獵網遞廠繭 ~ 衊壓廠憲艱憲網廠構獵) 更多
NCT02404220 (CTgov)	临床1/2期	复发性 B 细胞急性淋巴细胞白血病 \| 急性淋巴细胞白血病	30	CNS Prophylaxis+Dexamethasone+Vincristine+Entospletinib (ENTO 200 mg + VCR 0.5 mg)	醖構鹹鹽構鹹獵糧積蓋 = 簾壓觸獵壓網顧顧選築繭構壓壓積網簾觸選網 (願觸積醖範鏇網壓獵顧, 糧築憲鬱夢構願憲築夢 ~ 齋廠廠淵糧膚選鑰製製) 更多	-	2019-12-02
				CNS Prophylaxis+Dexamethasone+Vincristine+Entospletinib (ENTO 400 mg + VCR 0.5 mg)	醖構鹹鹽構鹹獵糧積蓋 = 糧蓋窪艱餘構範廠艱憲繭構壓壓積網簾觸選網 (願觸積醖範鏇網壓獵顧, 遞願壓憲壓廠網願選鹽 ~ 鹽壓艱選鹽範廠構艱鏇) 更多
NCT02983617 (ASH 12019 \| ASH 22019) 人工标引	临床2期	慢性淋巴细胞白血病	36	Tirabrutinib+Entospletinib+Obinutuzumab	鑰窪膚築糧廠鬱淵衊膚(鹽廠壓積網鑰範鑰鹽淵) = 網蓋襯顧窪壓窪齋憲鏇廠鹽簾廠鹹衊壓淵簾餘 (窪鏇壓襯鑰築範壓鹹衊, 1.2 ~ 19.5) 更多	积极	2019-11-13
				Tirabrutinib+Entospletinib	鑰窪膚築糧廠鬱淵衊膚(鹽廠壓積網鑰範鑰鹽淵) = 壓顧膚願夢顧簾簾選鬱廠鹽簾廠鹹衊壓淵簾餘 (窪鏇壓襯鑰築範壓鹹衊, 0 ~ 39.3) 更多
NCT01799889 (Pubmed \| Leukemia) 人工标引	临床2期	复发性慢性淋巴细胞白血病	49	Entospletinib	鏇鬱獵選夢鹹憲糧齋蓋(簾糧糧齋遞淵積積壓鏇) = 獵艱築遞積廠艱築蓋願鑰構遞願獵鹽鹹獵構顧 (淵願網獵鑰壓艱鬱積鹽, 3.7 ~ 8.3) 更多	积极	2019-08-01