A phase IIa, multi-center, randomized, double-blind, vehicle-controlled study to determine antipsoriatic efficacy and safety of topical CEP-701 (lestaurtinib) cream formulations in patients with psoriasis vulgaris - POC Psoriasis

开始日期2008-10-17

申办/合作机构

Perrigo Israel Pharmaceuticals Ltd.

EUCTR2005-002258-23-DE

/ Not yet recruitingN/A

A Randomized, Open Label Study of Oral CEP-701 Administered in Sequence With Standard Chemotherapy to Patients With Relapsed Acute Myeloid Leukemia (AML) Expressing FLT 3 Activating Mutations - NA

开始日期2008-01-23

申办/合作机构

Cephalon, Inc.

NCT00557193

/ Completed临床3期IIT

A Phase III Study of Risk Directed Therapy for Infants With Acute Lymphoblastic Leukemia (ALL): Randomization of Highest Risk Infants to Intensive Chemotherapy +/- FLT3 Inhibition (CEP-701, Lestaurtinib; NSC#617807)

This phase III trial studies combination chemotherapy with or without lestaurtinib with to see how well they work in treating younger patients with newly diagnosed acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of stop cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without lestaurtinib in treating acute lymphoblastic leukemia.

开始日期2008-01-15

申办/合作机构

The Children's Oncology Group Foundation, Inc.

[+1]

100 项与来他替尼相关的临床结果

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100 项与来他替尼相关的转化医学

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100 项与来他替尼相关的专利（医药）

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392

项与来他替尼相关的文献（医药）

2025-09-01·Journal of Computational Biophysics and Chemistry

Deciphering the Selective Targeting of Noncovalent, Wild Type-sparing, and ATP-competitive Tyrosine Kinase Inhibitors to EGFR T790M Gatekeeper Mutant

作者: Wang, Jing ; Wu, Hongyan ; Cheng, Jin ; Meng, Shu

Various tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for cancer therapy. However, many patients treated with first-line TKIs are clinically observed to eventually establish a gatekeeper T790M mutation in the ATP-binding site of the EGFR kinase domain, which is primarily responsible for acquired drug resistance to cancers. Over the past decades, a number of noncovalent, wild-type-sparing and ATP-competitive inhibitors (NWAIs) were reported to selectively target the T790M mutant over wild-type kinase, which are independent of the traditional inhibitor classification system that categorizes EGFR TKIs into four generations. Here, we systematically investigated the intermolecular interaction of wild-type EGFR (EGFRWT) and its T790M mutant (EGFRT790M) with 15 existing NWAI inhibitors, paying attention to the structural and energetic responses of inhibitor ligands to the gatekeeper mutation. It was revealed that the NWAIs can be typed into three classes I, II and III, which can form S[Formula: see text] interactions, hydrophobic (van der Waals) contacts and weak hydrogen (halogen) bonding with the side-chain thioether moiety of the mutant Met790 residue, respectively, thus conferring additional affinity and specificity to inhibitor ligands upon the T790M mutation. In addition, we further performed 2D-chemical similarity search to identify new class I NWAIs, from which two Staurosporine analogs (i.e. UCN01 and ZHD0501) were identified to have a good selectivity for EGFRT790M over EGFRWT. They can be exploited as promising leading chemical scaffolds to further develop potent, selective, wild-type-sparing NWAI inhibitors of EGFRT790M gatekeeper mutant.

2025-03-18·ANALYTICAL CHEMISTRY

High-Throughput Empirical and Virtual Screening To Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

Article

作者: Shih, Chien-Hung ; Chen, Yu-Chih ; Chen, Hsiao-Chun ; Ma, Yushu ; Brown, Daniel D. ; Zhang, Yuan ; Wang, Li-Ju ; Cheng, Jinxiong ; Tan, Yanhao ; Lee, Adrian V. ; Oesterreich, Steffi ; Chiu, Yu-Chiao

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirical testing of all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated five compounds as potent PGCC inhibitors using cell lines and patient-derived models. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.

2025-03-01·STAR protocols

Protocol to infer off-target effects of drugs on cellular signaling using interactome-based deep learning

Article

作者: Lauffenburger, Douglas A ; Nilsson, Avlant ; Meimetis, Nikolaos

Drugs that target specific proteins often have off-target effects. We present a protocol using artificial neural networks to model cellular transcriptional responses to drugs, aiming to understand their mechanisms of action. We detail steps for predicting transcriptional activities, inferring drug-target interactions, and explaining the off-target mechanism of action. As a case study, we analyze the off-target effects of lestaurtinib on FOXM1 in the A375 cell line. For complete details on the use and execution of this protocol, please refer to Meimetis et al.¹.

项与来他替尼相关的新闻（医药）

2024-11-28

·精准药物

共价药物体外时间依赖性抑制（TDI）数据分析和解读

前言共价药物（Covalent drug）是指在结构中包含反应性的官能团，能与靶蛋白形成共价键，实现与靶蛋白长期结合，从而提供独特的药效学特征。从偶然发现到目标性设计，共价药物在多个疾病领域蓬勃发展，尤其是抗肿瘤领域。自KRAS靶点在癌症中的作用被发现以来，近30年间研究者使用传统药物发现方法一直没有突破这一靶点的不可成药性，而共价抑制剂Sotorasib（Lumakras）和Adagrasib（Krazati）打破了KRAS“不可成药靶点”的魔咒。近年来，多款共价药物成功上市，包括针对EGFR、BTK、KRAS等靶点的抑制剂。细胞色素P450酶（以下简称CYP酶）是体内参与药物代谢最广泛的I相代谢酶，主要位于肝脏，参与约75%的小分子药物代谢。药物对CYP酶的抑制会引起联用药物的暴露量增加或活性代谢产物暴露量减少，造成潜在毒性或影响疗效。抑制评价分为可逆性抑制（Reversible inhibition）和时间依赖性抑制（Time-dependent inhibition, TDI）评价，其中TDI会造成更为严重的药物相互作用（Drug interaction, DDI）。药物本身或其代谢后生成的反应性中间体与CYP酶的共价结合是TDI发生的机理之一，那么共价药物是否一定会发生TDI呢？共价药物的TDI风险比非共价抑制剂更高吗？如何评估TDI风险和解读TDI数据呢？本文分析了29个已上市的共价药物对CYP酶的TDI研究结果，并对体外TDI风险评估的方法和数据解读提供相关建议。上市共价药物对CYP450酶的抑制结果分析据报道，自1947年以来共117种共价药物获批[1]，已上市的共价药物主要涉及抗感染（青霉素、磷霉素）、抗病毒（奈马特韦）和抗肿瘤（奥西替尼、达克替尼）等治疗领域。本文检索了自2000年以来上市的共价药物对CYP酶的体外TDI结果，共整理出29个共价药物的数据，详见文末附表1。其中19个共价药物对至少一种CYP酶表现出TDI，约占65.5%。TDI在7种常见CYP酶的分布汇总如图1，有15个药物对CYP3A存在TDI，约占79%；其次是2C8，5个共价药物对其存在TDI，约占26%；对1A2和2B6存在TDI的共价药物都为3个，占比约16%；有1个共价药物对2C19存在TDI，占比约5%。19个共价药物对2C9和2D6不存在TDI或目前未见报道。图1. 自2000年之后上市的具有TDI的共价药物在常见CYP酶的分布情况一项体外[22]研究评估了14个蛋白激酶抑制剂对CYP2C8和CYP3A的TDI，结果表明经过与NADPH预孵育以后，11个激酶抑制剂对CYP3A的抑制效果增强，3个对CYP2C8的抑制效果增强，（如图2）。其中有8个已被文献报道为CYP3A的TDI抑制剂，另外3个在随后的研究中证实抑制CYP3A的IC50偏移率大于2倍。这14个药物并非共价药物，由此看来，非共价药物尤其是蛋白激酶抑制剂的TDI风险依然不容忽视。对于共价药物和非共价药物，TDI都是需要重点关注的内容。图2. 蛋白激酶抑制剂与NADPH预孵育30min后抑制阿莫地喹N-去乙基化（CYP2C8）和咪达唑仑1'-羟化（CYP3A）的结果。BOSU, bosutinib; BOSU iso, bosutinib isomer 1; CRIZ, crizotinib; DASA, dasatinib; ERLO, erlotinib; GEFI, gefitinib; LEST, lestaurtinib; NILO, nilotinib; PAZO, pazopanib; SARA, saracatinib; SORA, sorafenib; SUNI, sunitinib. [22] 体外TDI风险评估的方法建议监管机构和制药公司已经认识到评估TDI风险的重要性，人用药品技术要求国际协调理事会（ICH）发布的指导原则M12《Drug Interaction Studies》[23]于今年5月21日最终采纳。结合指南推荐，体外评估药物TDI风险的方法总结如下： “ 1 酶活性损失百分比、假一级速率常数kobs和IC50偏移早期药物发现阶段，需要高通量、快速筛选确定CYP酶的TDI潜力，可以通过单一化合物浓度下含和不含NADPH预孵育后损失百分比（%Activity loss），CYP酶活性降低（kobs）或多浓度的化合物含和不含NADPH预孵育后IC50值的偏移(IC50 shift)来判断化合物是否有TDI潜力。 “ 2 TDI抑制的动力学常数测定（kinact、KI）评估CYP酶TDI的重要动力学常数包括最大失活速率常数（kinact）、导致半数最大失活的抑制剂浓度（KI）。采用不同浓度的化合物（至少6个）与酶源（即肝微粒体、肝细胞、重组酶系统）及NADPH进行第1次孵育（至少6个时间点），也称失活孵育；在特定的孵育时间后，将失活孵育混合物加入含有CYP同工酶探针底物的二次孵育当中，反应一定时间后，终止反应，并测量探针底物的代谢产物生成。计算失活后相对于没有抑制剂时所测得的活性的剩余百分比，剩余百分比与失活孵育的时间进行线性拟合作图，得到一系列一级衰减曲线，如图3a，直线斜率的负值即为一个浓度点的表观抑制速率（kobs）。用不同浓度下的表观抑制速率与化合物的浓度进行非线性拟合即可计算得到kinact和KI，如图3b。图3. Verapamil的体外TDI动力学常数测定（kinact和KI）测量kinact和KI的体外实验方法通常不适合早期药物发现项目中的高通量筛选。但从药物发现的角度，较大的kinact值和较小的KI值通常会增加CYP酶失活导致DDI的可能性。因此在临床前药物发现中，也可以通过kinact/KI比值衡量化合物CYP酶失活的效率，对同系列化合物进行排序。案例分享与TDI数据的解读建议 Ritlecitinib是一种共价JAK3酪氨酸激酶抑制剂，主要用于治疗脱发症，尤其是斑秃和非节段型白癜风（NSV）。其共价抑制机制主要通过与JAK3催化域中的半胱氨酸残基（Cys-909）发生不可逆的共价结合来实现。这一残基在其他JAK家族成员中被丝氨酸残基所取代，这使得Ritlecitinib对JAK3具有高度的选择性[24, 25]。 Ritlecitinib在体外肝微粒体TDI评价体系中，被评估为CYP1A2和CYP3A的TDI抑制剂。其中，Ritlecitinib对CYP1A2（以咖啡因底物）代谢活性抑制常数分别是KI为327 μmol/L，kinact为0.0917 min-1。由于在测试的浓度范围内（3-200 μmol/L）未达到抑制饱和，因此无法确定对CYP3A（以咪达唑仑底物）代谢活性的KI或kinact，但kinact/KI估计为0.871 mL/min/μmol[20]。在斑秃患者中，每日一次口服50 mg的Ritlecitinib后最大稳态游离药物浓度（Cmax,u）估计值1.1 μmol/L[20]，结合上述体外TDI参数，根据ICH M12指导原则[23]的基本方法初步评价TDI风险如表1。计算得到Ritlecitinib对CYP1A2的表观一级失活速率常数(Kobs)为0.001517 min-1。Kdeg是酶的表观一级降解速率常数，引用自指导原则，计算（kobs+kdeg）/kdeg的值为6.06，大于1.25，说明需关注Ritlecitinib潜在临床抑制风险。表1. 基本模型预测Ritlecitinib对CYP1A2的TDI风险注：kobs=(kinact*5*Cmax,u)/(KI+5*Cmax,u)，此处计算所使用数据引用自文献[20] 该药物开展了相应的临床DDI研究。Liu[26]等人在健康志愿者中开展的临床研究中发现，咖啡因（CYP1A2底物）与Ritlecitinib联合使用时，咖啡因的AUC和Cmax分别增加了约165%和10%，表明Ritlecitinib是CYP1A2的中等抑制剂，可以增加CYP1A2底物的暴露量。Ritlecitinib与CYP酶底物合用的临床DDI研究结果汇总如表2，Ritlecitinib与咪达唑仑（CYP3A底物）合用导致咪达唑仑的AUC和Cmax分别增加了约169%和81%，而其与Efavirenz（CYP2B6底物）和Tolbutamide（CYP2C底物）合用后，底物的暴露量变化不具有临床意义[27]。在Ritlecitinib药品说明书中，提示与CYP3A和CYP1A2的底物合用时，可能增加不良反应风险，需考虑额外的监测或调整剂量。表2. Ritlecitinib临床与CYP酶底物合用引起的暴露量变化 c: 合用Ritlecitinib相比于单独给药的Cmax和AUCinf的比值。 d: 报告了Efavirenz的AUC0-72。以上结果整理自药品说明书。 TDI数据解读建议药物研发早期可通过单一浓度下的酶活性降低(酶活性损失率%Activity loss或假一级速率常数kobs或多浓度点下IC50偏移(≥1.5)，检测化合物的TDI潜力；如药物具有TDI潜力，可通过体外研究获得TDI的动力学参数kinact、KI，结合人体PK数据，应用模型排除或预测临床TDI风险。结语本文整理的数据表明65%以上的共价药物表现出对CYP酶的TDI，而文献显示非共价药物如蛋白激酶抑制剂的TDI风险同样不容忽视，因此，不论是否为共价药物，均建议在研发早期考察TDI风险。 TDI引起的临床不良反应往往是极其严重的，如米贝拉地尔的撤市，其作为CYP3A的强TDI抑制剂，与其他3A的底物合用会引起严重的毒性反应，严重时导致死亡。对于存在TDI风险的药物，必要时通过体外实验获取抑制动力学参数kinact和KI，结合临床PK数据进行临床DDI风险的评估，如果体外数据和模型无法排除临床抑制风险，则应使用敏感探针底物进行临床DDI研究。药明康德DMPK已经建立了一套专门针对共价药物的药代动力学研究体系，其中包括早期的高通量筛选、共价药物多样化的体内外代谢模型与方法、丰富的体外ADME试验类型、以及14C标记化合物的合成和相应的ADME技术平台，可以支持客户加速共价药物的研发和申报。附表1. 29个共价药物对CYP酶的TDI结果汇总（下滑查看更多） a: 结果引用自药品说明书。 b: 由于测试浓度（3-200 μM）下抑制未被饱和，无法计算准确KI和kinact值。参考文献： [1] Journal of Medicinal Chemistry 2022 65 (8),5886-5901 DOI: 10.1021/acs.jmedchem.1c02134 [2] Suchy D, Łabuzek K, Stadnicki A, Okopień B. Ezetimibe--a new approach in hypercholesterolemia management. Pharmacol Rep. 2011;63(6):1335-48. doi: 10.1016/s1734-1140(11)70698-3. PMID: 22358082. [3] Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes；Drug Metab Dispos. 2006 Apr;34(4):702-8. [4] M. F Moghaddam, et al. Drug Metabolism Letters, 2014, 8, 19-30. [5] NDA 22-134: https://www.fda.gov/files/drugs/published/22134-Alcaftadine-ClinPharm-PREA.pdf [6] Chapron B, Risler L, Phillips B, Collins C, Thummel K, Shen D. Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes. J Pharm Pharm Sci. 2015;18(1):101-11. doi: 10.18433/j3288c. PMID: 25877445. [7] Wang, Z., Yang, J., Kirk, C., Fang, Y., Alsina, M., Badros, A., Infante, J. R. (2012). Clinical Pharmacokinetics, Metabolism, and Drug-Drug Interaction of Carfilzomib. Drug Metabolism and Disposition, 41(1), 230–237. doi:10.1124/dmd.112.047662 [8] Jordi Aubets et,al; No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P‐glycoprotein (P‐gp) drug transporter;Pharmacol Res Perspect. 2019 Dec; 7(6): e00540. [9] NDA 206829: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206829orig1s000clinpharmr.pdf [10] DMD Fast Forward. Published on March 10, 2014 as DOI: 10.1124/dmd.113.055335 [11] Evaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP‐5862, Using a Physiologically‐Based Pharmacokinetic Modeling Approach; CPT Pharmacometrics Syst Pharmacol. 2019 Jul; 8(7): 489–499. [12] NDA 209776: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000PharmR.pdf [13] Report on the Deliberation Results: https://www.pmda.go.jp/files/000240418.pdf [14] Zhang H, Ou YC, Su D, Wang F, Wang L, Sahasranaman S, Tang Z. In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor. Pharmacol Res Perspect. 2021 Dec;9(6):e00870. doi: 10.1002/prp2.870. PMID: 34664792; PMCID: PMC8524670. [15] Report on the Deliberation Results: https://www.pmda.go.jp/files/000237315.pdf [16] NDA 214665: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf [17] NDA 215301: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215310Orig1s000MultidisciplineR.pdf [18] KRAZATI 200 mg film-coated tablets: ANNEX I [19] Heather Eng et al, Disposition of Nirmatrelvir, an Orally Bioavailable Inhibitor of SARS-CoV-2 3C-Like Protease, across Animals and Humans; Drug Metab Dispos. 2022 May;50(5):576-590. [20] Litfulo review report; https://www.pmda.go.jp/files/000266925.pdf [21] https://www.ema.europa.eu/en/documents/rmp-summary/skyclarys-epar-risk-management-plan_en.pdf [22] Drug Metab Dispos 42:1202–1209, July 2014, http://dx.doi.org/10.1124/dmd.114.057695 [23] ICH M12《Drug Interaction Studies》 [24] Xu H, Jesson MI, Seneviratne UI, et al. PF-06651600, a dual JAK3/TEC family kinase inhibitor. ACS Chem Biol. 2019;14(6):1235–42. [25] Telliez JB, Dowty ME, Wang L, et al. Discovery of a JAK3- selective inhibitor: functional diferentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem Biol. 2016;11(12):3442–51. [26] Liu J, Solan R, Wolk R, et all. Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants. Br J Clin Pharmacol. 2023;89:2208–2215. [27] Pfzer Inc. LITFULO™ (ritlecitinib) capsules, for oral use: US prescribing information. 2023. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed 26 Jul 2023. （下滑查看更多）作者：吴文萍，马虹莹，马利萍，周莹，金晶编辑：姜利芳，钱卉娟，陈根富设计：倪德伟，张莹莹声明：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↓

上市批准一致性评价医药出海

2023-12-14

·SYNAPSE

Deciphering NTRK Inhibitors and Keeping Up with Their Recent Developments

NTRK, also known as neurotrophic receptor tyrosine kinase, plays a crucial role in the human body. It is a family of proteins that are involved in the growth, development, and survival of nerve cells. NTRK receptors are activated by neurotrophins, which are a group of proteins that support the growth and maintenance of neurons. When NTRK receptors are activated, they initiate signaling pathways that regulate various cellular processes, including cell growth, differentiation, and survival. Dysregulation of NTRK signaling has been implicated in various diseases, including cancer and neurological disorders. Targeting NTRK receptors has emerged as a promising therapeutic approach in the pharmaceutical industry. All currently available NTRK inhibitors are Tropomyosin receptor kinase (Trk) inhibitors, some of which also have anti-ROS1 and ALK activity. NTRK inhibitors bind to Trk, thereby preventing ligand-Trk interaction and Trk activation, thus blocking the oncogenic activity of cancer cells overexpressing NTRK fusion proteins, thereby inducing cell apoptosis and inhibiting cell growth in tumor cells. Similar to other TKIs, the durability of first-generation NTRK inhibitors is often limited by mutations affecting NTRK inhibitor binding interactions, including primary and acquired resistance. Therefore, second-generation NTRK inhibitors have been developed to overcome these resistance mutations. Compared with first-generation NTRK inhibitors, second-generation NTRK inhibitors have a smaller molecular weight and a compact macrocyclic structure, which avoids the steric hindrance that prevents first-generation NTRK inhibitors from binding to the ATP binding site in solvent front, gatekeeper, and xDFG mutations. The analysis of the target NTRK reveals a competitive landscape with multiple companies actively developing drugs targeting NTRK. Bayer AG, Roche Holding AG, Bristol Myers Squibb Co., Exelixis, Inc., and Ipsen SA are among the companies growing fastest under this target. The indications for NTRK-targeted therapies cover a wide range of cancers, indicating the potential of these therapies in treating various types of tumors. Small molecule drugs, Synthetic peptides, and Monoclonal antibodies are progressing rapidly, while biosimilars pose intense competition around innovative drugs. The countries/locations developing fastest under the target NTRK include the United States, European Union, Japan, and China, with China showing significant progress. Overall, the target NTRK presents a promising opportunity for the pharmaceutical industry, with potential for further growth and development in the future. How do they work? NTRK inhibitors are a type of medication that target and inhibit the activity of neurotrophic receptor tyrosine kinases (NTRKs). NTRKs are a family of proteins that play a crucial role in the growth, development, and survival of nerve cells. They are involved in various cellular processes, including cell proliferation, differentiation, and survival. When NTRKs become abnormally activated or overexpressed, it can lead to uncontrolled cell growth and contribute to the development and progression of certain types of cancers. NTRK inhibitors work by specifically blocking the activity of these receptors, thereby inhibiting the signaling pathways that promote tumor growth and survival. These inhibitors have shown promising results in the treatment of cancers that harbor NTRK gene fusions, which are genetic alterations that result in the fusion of NTRK genes with other genes. This fusion leads to the constitutive activation of NTRK receptors and the promotion of cancer cell growth. By targeting NTRK receptors, inhibitors can help suppress the growth of cancer cells and potentially improve patient outcomes. NTRK inhibitors are considered a targeted therapy and are typically used in patients with advanced or metastatic cancers that have NTRK gene fusions. They may be prescribed as a standalone treatment or in combination with other anticancer therapies, depending on the specific cancer type and individual patient characteristics. List of NTRK Inhibitors The currently marketed NTRK inhibitors include: Repotrectinib Entrectinib Larotrectinib Sulfate Cabozantinib (s)-Malate Regorafenib Taletrectinib Lestaurtinib Tavilermide AK-1830 BEN-2293 For more information, please click on the image below. What are NTRK inhibitors used for? NTRK inhibitors are primarily used in certain rare tumors, such as infantile fibrosarcoma and secretory breast cancer. For more information, please click on the image below to log in and search. How to obtain the latest development progress of NTRK inhibitors? In the Synapse database, you can keep abreast of the latest research and development advances of NTRK inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

2023-11-29

·SYNAPSE

Unveiling the Secrets of JAK2 Inhibitors: Stay Updated with the Latest Advances?

JAK2, or Janus kinase 2, is an enzyme that plays a crucial role in the human body's signaling pathways. It is primarily involved in the activation of cytokine receptors, which are responsible for regulating various cellular processes. JAK2 is particularly important in hematopoiesis, the process of blood cell formation, as it is involved in the signaling of several key cytokines that control the production and differentiation of blood cells. Dysregulation or mutations in JAK2 can lead to various hematological disorders, including myeloproliferative neoplasms. Understanding the role of JAK2 is essential for developing targeted therapies to treat these disorders and potentially other diseases influenced by cytokine signaling. Janus kinase 2 (JAK2) inhibitors are a type of medication that modulates the immune system by inhibiting the activity of the JAK2 enzyme, thereby interfering with the JAK-STAT signaling pathway in lymphocytes. They have revolutionized treatments for a range of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases. The development of JAK2 inhibitors began with the identification of potential inhibitors that work by blocking its tyrosine gated ATP binding site. The first JAK inhibitor to reach clinical trials was tofacitinib, a specific inhibitor of JAK3 that also inhibits JAK1 and JAK2 to a lesser extent. The analysis of the current competitive landscape and future development of target JAK2 reveals a diverse range of companies, indications, drug types, and countries/locations involved in the development of JAK2-targeted drugs. Companies such as Incyte Corp., Eli Lilly & Co., Novartis AG, AbbVie, Inc., Pfizer Inc., GSK Plc, Bristol Myers Squibb Co., Swedish Orphan Biovitrum AB, Astellas Pharma, Inc., and Roche Holding AG are growing fastest under the current target, with drugs in various stages of development. The approved indications for JAK2-targeted drugs cover a wide range of diseases and conditions, indicating the potential therapeutic value of these drugs. Small molecule drugs and chemical drugs are progressing most rapidly, suggesting intense competition in the market. The countries/locations developing fastest include the United States, European Union, Japan, Norway, Liechtenstein, Iceland, China, Australia, Canada, United Kingdom, Switzerland, India, Kuwait, Spain, South Korea, Germany, Italy, France, Poland, and Israel. The progress in China highlights the country's growing presence in the pharmaceutical industry. Overall, the analysis indicates a competitive landscape and a promising future for the development of JAK2-targeted drugs. How do they work?JAK2 inhibitors are a type of medication that target the Janus kinase 2 (JAK2) enzyme. JAK2 is a protein involved in the signaling pathway of various cytokines and growth factors, playing a crucial role in the regulation of immune responses and blood cell production. These inhibitors work by blocking the activity of JAK2, thereby reducing the production of certain inflammatory mediators and suppressing abnormal cell growth. From a biomedical perspective, JAK2 inhibitors are primarily used in the treatment of myeloproliferative neoplasms (MPNs), a group of blood disorders characterized by the overproduction of blood cells. One of the most well-known MPNs is polycythemia vera, where there is an excessive production of red blood cells. JAK2 inhibitors help to control the symptoms associated with these disorders, such as enlarged spleen, fatigue, and blood clotting complications. Furthermore, JAK2 inhibitors have shown promise in the treatment of certain autoimmune diseases, such as rheumatoid arthritis and psoriasis, as well as in certain types of cancers, including certain forms of leukemia. By targeting the JAK2 enzyme, these inhibitors can help modulate the immune response and inhibit the abnormal cell growth associated with these conditions. It is important to note that JAK2 inhibitors are prescription drugs and should only be used under the guidance of a healthcare professional. They may have potential side effects, such as an increased risk of infections, anemia, and liver toxicity. Regular monitoring and follow-up with a healthcare provider are necessary while using JAK2 inhibitors to ensure their safe and effective use. List of JAK2 InhibitorsThe currently marketed JAK2 inhibitors include: Momelotinib DihydrochloridePacritinibFedratinib HydrochlorideUpadacitinibPeficitinib HydrobromideBaricitinibTofacitinib CitrateRuxolitinib PhosphateDeuterated RuxolitinibLestaurtinib For more information, please click on the image below. What are JAK2 inhibitors used for?JAK2 inhibitors are primarily used in the treatment of myeloproliferative neoplasms (MPNs) For more information, please click on the image below to log in and search. How to obtain the latest development progress of JAK2 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of JAK2 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与来他替尼相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D04696	来他替尼	-	DB06469

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
急性淋巴细胞白血病	临床3期	美国	-	-
急性淋巴细胞白血病	临床3期	澳大利亚	-	-
急性淋巴细胞白血病	临床3期	加拿大	-	-
急性淋巴细胞白血病	临床3期	新西兰	-	-
急性淋巴细胞白血病	临床3期	-	Cephalon, Inc.	-
急性淋巴细胞白血病	临床3期	-	Kyowa Kirin Co., Ltd.	-
真性红细胞增多症	临床2期	美国	Cephalon, Inc.	2007-12-01
原发性血小板增多症	临床2期	美国	Cephalon, Inc.	2007-12-01
骨髓纤维化	临床2期	美国	Cephalon, Inc.	2007-06-01
复发性多发性骨髓瘤	临床2期	美国	Cephalon, Inc.	2006-04-01

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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


NCT00469859 (CTgov)	临床1/2期	复发性急性髓细胞白血病	14	lestaurtinib+Cytarabine+Idarubicin (Group 1 (Lestaurtinib Dose 50 mg/m2)	網選鹹壓鹹膚齋廠網齋 = 廠蓋積衊鬱淵鏇餘夢鏇觸鬱遞壓製憲鏇觸遞鹽 (醖觸壓鏇鬱願鹽遞積鬱, 積廠膚醖顧鏇齋選觸網 ~ 糧蓋衊顧廠鬱艱範艱鏇) 更多	-	2013-12-20
NCT00469859 (CTgov)	临床1/2期	复发性急性髓细胞白血病	14	lestaurtinib+Cytarabine+Idarubicin (Group 2 (Lestaurtinib: Dose 62.5 mg/m2)	網選鹹壓鹹膚齋廠網齋 = 夢淵鹹願艱製襯糧廠製觸鬱遞壓製憲鏇觸遞鹽 (醖觸壓鏇鬱願鹽遞積鬱, 鑰積膚網艱遞獵夢遞顧 ~ 顧壓廠蓋鏇鑰築夢膚廠) 更多	-	2013-12-20
NCT00494585 (CTgov)	临床2期	骨髓纤维化 \| 白血病	27	CEP-701	鏇夢觸廠製觸願醖衊齋 = 範網築艱夢顧艱鹽構淵衊壓願鏇餘範醖糧製鹽 (鹹製構憲築簾窪蓋糧襯, 膚醖醖淵鏇齋醖願網齋 ~ 膚夢鹽襯壓鹽網鹽淵範) 更多	-	2011-05-04
NCT00079482 (Pubmed \| Blood)	临床2期	急性髓性白血病	224	Chemotherapy alone	遞鹽製艱艱鏇壓膚淵衊(齋簾蓋構築積網顧鏇鏇) = 廠淵淵簾壓鑰構網醖憲遞範淵齋遞襯築蓋蓋蓋 (壓觸願餘築製鑰積鹹衊 )	不佳	2011-03-24
NCT00079482 (Pubmed \| Blood)	临床2期	急性髓性白血病	224	Chemotherapy followed by lestaurtinib	遞鹽製艱艱鏇壓膚淵衊(齋簾蓋構築積網顧鏇鏇) = 觸廠餘鹹膚壓鑰餘衊膚遞範淵齋遞襯築蓋蓋蓋 (壓觸願餘築製鑰積鹹衊 )	不佳	2011-03-24
ASCO2010	临床1期	难治性神经母细胞瘤	47	Lestaurtinib	襯艱鏇網製憲醖顧齋鑰(構鑰鹹夢簾網襯獵淵製) = 蓋願糧衊鹽獵範構簾範網鹽願齋獵鬱簾觸鏇齋 (憲淵餘範鏇築鏇夢製壓 )	-	2010-05-20
NCT00494585 (Pubmed \| Blood)	临床2期	原发性血小板增多症后骨髓纤维化 JAK2(V617F)-positive	22	CEP-701 80 mg	艱餘鏇糧顧廠壓範製簾(醖選觸簾積遞襯遞艱積) = diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27% 範衊範鏇衊鹹築齋襯艱 (遞範鬱構蓋顧鹹鹽積觸 ) 更多	-	2010-02-11