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更新于：2025-02-12

Saracatinib

塞卡替尼

更新于：2025-02-12

概要

基本信息

药物类型

小分子化药

别名

Saracatinib (USAN/INN)、Saracatinib difumarate、AZD 0530

+ [1]

靶点

FYN x SRC family

作用机制

FYN抑制剂(Fyn激酶抑制剂)、原癌基因酪氨酸蛋白激酶Src家族抑制剂

治疗领域

神经系统疾病呼吸系统疾病皮肤和肌肉骨骼疾病+ [2]

在研适应症

骨化性肌炎阿尔茨海默症特发性肺纤维化+ [1]

非在研适应症

晚期非小细胞肺癌晚期恶性实体瘤酗酒+ [69]

原研机构

AstraZeneca PLC

在研机构

阿斯利康制药有限公司

National Institutes of Health

Foundation For Neglected Disease Research

+ [1]

非在研机构

National Institute on Alcohol Abuse & Alcoholism

National Cancer Institute

Yale University

+ [6]

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)无进展

特殊审评孤儿药 (美国)

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结构/序列

分子式C27H32ClN5O5

InChIKeyOUKYUETWWIPKQR-UHFFFAOYSA-N

CAS号379231-04-6

关联

项与塞卡替尼相关的临床试验

NCT04307953

/ Recruiting临床2期IIT

Saracatinib Trial TO Prevent FOP

This is a phase 2 study, designed as a European multicentre 6-month double blind random-ized controlled trial (RCT) of AZD0530 versus matched placebo, followed by a 12 month trial comparing open-label extended AZD0530 treatment with historical control data.
Study population: Male and female adult patients aged 18 years and older with a diagnosis of FOP who meet the inclusion (active disease) and exclusion criteria will be eligible for participation in this study. The total number of enrolled patients will be 20.
Intervention: Patients will be randomized to receive either AZD0530 100mg once daily or matched placebo, taken orally for the first 6 months, immediately followed by an open-label extension in which all patients will receive AZD0530 100mg once daily oral dose for a further 12 months.
Endpoints: Endpoints include objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) , [18F] NaF Positron Emission Tomography (PET) activity and patient reported outcome measures.

开始日期2020-08-05

申办/合作机构

Stichting Onderzoek Cancer Center Amsterdam

[+6]

NCT03661125

/ Unknown status早期临床1期

A Randomised, Balanced, Double-blind Two-way Crossover Design Study to Evaluate the Effects of SRC Kinase Inhibitor, Saracatinib, on Brain Activity Associated With Visual Processing in Patients With Parkinson's Disease Psychosis.

Parkinson's disease is often characterised by movement symptoms such as rigidity and bradykinesia, however, there are a number of non-motor symptoms that can have a significant impact on quality of life. One of the most common non-motor symptoms of Parkinson's disease is visual hallucinations (where someone sees things that don't exist outside their mind). . Recent findings led to the approval of a drug called Pimavanserin as a treatment for PD psychosis in the USA. Based on other recent studies, we believe that Saracatinib, a drug that interacts within the same system as Pimavanserin, is a potential treatment for PD psychosis. Saracatinib has shown to reduce the intensity of the psychedelic effect induced by psilocybin (a naturally occurring psychedelic found in psilocybe mushrooms) and attenuate social cognition and brain changes in healthy volunteers. The aim of this study is to test the effects of 14 days dosing of saracatinib or placebo on 30 volunteers with PD psychosis. We aim to to use neuroimaging combined with psychopharmacology to provide evidence that a putative new treatment approach can modulate abnormal visual cortex activation in patients with PD psychosis. If positive, this proof of mechanism study would provide a strong platform to pursue symptom modification studies with Saracatinib.

开始日期2019-04-11

申办/合作机构

King's College London

[+2]

NCT02955186

/ Completed临床2期IIT

Fyn Kinase Inhibitors and Alcohol Drinking

The purpose of this study is to evaluate the effects of the study medication, saracatinib/AZD0530 (placebo or 125 mg/day) on alcohol drinking behavior in a laboratory setting in which participants are given an initial drink of alcohol followed by the choice to drink up to 12 more drinks over a three-hour period. The investigators hypothesize that saracatinib will reduce craving and number of drinks consumed prior to and after exposure to the initial drink of alcohol and during the three hour drinking period.

开始日期2017-05-09

申办/合作机构

Yale University

[+1]

100 项与塞卡替尼相关的临床结果

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100 项与塞卡替尼相关的转化医学

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100 项与塞卡替尼相关的专利（医药）

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650

项与塞卡替尼相关的文献（医药）

2025-01-07·COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING

A Novel Prognostic Risk Model Based on Oxidative Stress to Predict Survival and Improve Treatment Strategies in Stomach Adenocarcinoma

Article

作者: Li, Xuezhi ; Qu, Xiaodong ; Zhang, Jie ; Yao, Nuo ; Li, Songbo ; Shi, Yongquan ; Zhao, Xingyu ; Lin, Kexin

Background::

Stomach adenocarcinoma (STAD) is the fifth most common tumor worldwide, imposing a significant disease burden on populations, particularly in Asia. Oxidative stress is well-known to play an essential role in the occurrence and progression of malignancies. Our study aimed to construct a prediction model by exploring the correlation between oxidative stress-related genes and the prognosis of patients with STAD.

Method::

STAD data from TCGA were used to identify the differentially expressed oxidative stress-related genes (OSGs), with data from GEO serving as the validation cohort. Univariate Cox and LASSO regression analyses were performed to select prognosis-related genes for the risk model, which was then integrated with clinical features into a nomogram. The physiological functions and pathways of these identified genes were explored using GO and KEGG analyses. After evaluating the prediction value of the prognostic model in the GEO cohort, drug sensitivity and immune infiltration were comprehensively analyzed using R. Expression levels of the prognostic genes were verified by quantitative real-time PCR in gastric cancer and paired normal tissues.

Results::

Cox regression and LASSO regression analysis identified SERPINE1, VHL, CD36, NOS3, ANXA5, ADCYAP1, POLRMT and GPX3 as the signature genes from 160 differentially expressed OSGs. Both Kaplan–Meier survival analysis and ROC curve at 5 years in the TCGA and the GEO cohort exhibited great predictive ability of the prognostic model, with the AUC >0.7 in TCGA. Validated as an independent risk factor, the model was integrated with clinicopathological variables (including age, stage, and gender) to build a nomogram for more accurate risk stratification. Moreover, therapy sensitivity analysis between the low- and high-risk categories showed that those who scored higher would benefit more from BEZ235, Dasatinib, Pazopanib, and Saracatinib. Meanwhile, differences in the tumor environment, immune infiltration and response to immunotherapy between the two groups were noted. Finally, qRT-PCR validated the differential expression of these genes in STAD and paired normal tissues.

Conclusion::

Our study has effectively established an oxidative stress-related prognostic model, providing a promising tool for personalized clinical strategies and improved STAD patient outcomes.

2025-01-01·GENE

The immunomodulatory role of the MAFB gene in hepatocellular carcinoma and its impact on biological activities

Article

作者: Qi Han, An ; Zhang, Yan ; Yang, Mingya ; Zhu, Li-Xin ; Zhang, Chao ; Han, Anqi ; Yi Sun, Hai ; Zhang, Li ; Wang, Zhenzhen ; Meng, Tao ; Zhen Wang, Zhen ; Wei Zuo, Jia ; Ya Yang, Ming ; Xu, Na ; Liu, Yu ; Zhou, Yang-Liu ; Sun, Haiyi ; Zuo, Jiawei

OBJECTIVE:

The transcription factor MAFB is part of the MAF family and is known to promote hepatocellular carcinoma (HCC) by upregulating cyclin D1. However, its role in HCC immunity and prognosis remains unclear. This study explores the biological function, prognostic significance, and immune impact of MAFB in HCC.

METHODS:

Immunohistochemistry was used to analyze MAFB expression in HCC and adjacent non-tumor tissues. RT-qPCR and Western blotting measured MAFB levels in HCC cell lines. Specific siRNA was used to knockdown MAFB in HCCLM3 and MHCC97H cells, followed by assays to evaluate cell proliferation, migration, and colony formation. Data from the TCGA database and online tools TIMER and TISDB were used to assess the relationship between MAFB and immune responses. A prognostic model based on MAFB-related immune genes was established, and drug sensitivity analysis was performed.

RESULTS:

MAFB was significantly overexpressed in HCC tissues. Knockdown of MAFB in HCC cell lines reduced their proliferation and migration abilities. The risk model based on MAFB-related immune genes effectively predicted patient prognosis, supported by ROC curves. Gene set enrichment analysis indicated that MAFB is involved in immune-related pathways. Several drugs were identified as potentially sensitive to MAFB expression levels.

CONCLUSION:

MAFB plays a significant role in HCC development and immune regulation. The prognostic model combining MAFB-related immune genes provides valuable insights for predicting patient outcomes and identifying potential therapeutic targets.

2025-01-01·MOLECULAR NEUROBIOLOGY

Fyn Kinase in Alzheimer’s Disease: Unraveling Molecular Mechanisms and Therapeutic Implications

Review

作者: Meur, Shreyasi ; Karati, Dipanjan

Alzheimer's disease, characterized by the accumulation of abnormal protein aggregates and neuronal damage in the brain, leads to a gradual decline in cognitive function and memory. As a complex neurodegenerative disorder, it involves disruptions in various biochemical pathways and neurotransmitter systems, contributing to the progressive loss of neurons and synaptic connections. The complexity of Alzheimer's signaling pathways complicates treatment, presenting a formidable challenge in the quest for effective therapeutic interventions. A member of the Src family of kinases (SFKs), Fyn, is a type of non-receptor tyrosine kinase that has been linked to multiple essential CNS processes, such as myelination and synaptic transmission. Fyn is an appealing target for AD treatments because it is uniquely linked to the two major pathologies in AD by its interaction with tau, in addition to being activated by amyloid-beta (Aβ) through PrP^C. Fyn mediates neurotoxicity and synaptic impairments caused by Aβ and is involved in regulating the process of Aβ synthesis.Additionally, the tau protein's tyrosine phosphorylation is induced by Fyn. Fyn is also a challenging target because of its widespread body expression and strong homology with other kinases of the Src family, which could cause unintentional off-target effects. This review emphasizes signaling pathways mediated by Fyn that govern neuronal development and plasticity while also summarizing the most noteworthy recent research relevant to Fyn kinase's function in the brain. Additionally, the therapeutic inhibition of Fyn kinase has been discussed, with a focus on the Fyn kinase inhibitors that are in clinical trials, which presents a fascinating opportunity for targeting Fyn kinase in the creation of possible therapeutic approaches for the management of Alzheimer's disease.

项与塞卡替尼相关的新闻（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

2024-07-30

·Business Wire

New Study Describes a Functional, Aged, Human Cell-Based Platform That Examines the Contribution of Senescence in Alzheimer’s Disease Progression, and Response to Therapeutics

ORLANDO, Fla.--( BUSINESS WIRE )--Researchers from Hesperos and the University of Central Florida have developed a groundbreaking model using human induced pluripotent stem cell (iPSC)-derived cortical neurons to better understand and combat Alzheimer’s disease (AD). Their study, “ A functional aged human iPSC-cortical neuron model recapitulates Alzheimer’s disease, senescence, and the response to therapeutics ," has been published in the prestigious journal Alzheimer's & Dementia ® : The Journal of the Alzheimer's Association. doi.org/10.1002/alz.14044 AD affects an estimated 6.2 million Americans aged 65 and older, with projections suggesting this number could reach 14 million by 2050. Current treatments, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, provide only temporary relief. The high failure rate of AD clinical trials highlights the need for a better understanding of the pathophysiology and drug mechanisms. The study addresses a critical challenge in Alzheimer’s research: the degeneration of cortical layers associated with cognitive decline. Despite substantial efforts to date, few current AD therapies are not disease-modifying. The team accurately reproduced key biological aspects of aging and senescence in a multi-cellular microphysiological system (MPS), also known as a Human-on-a-Chip. This new approach reveals how cellular aging, also known as senescence, contributes to disease progression and therapy resistance, providing researchers with an accurate, human platform to further understand the disease and potential therapeutics in a living context. Further, since other platforms at Hesperos, based on neurodegenerative diseases, have been accepted by the Food and Drug Administration (FDA) for efficacy data, it provides a new method to accelerate development and regulatory submissions of new treatments. This model provides an invaluable tool for real-time measurement of neuronal activity and aging biomarkers, facilitating drug screening and the development of AD therapies. It also reveals complex disease mechanisms, such as the role of inflammatory factors in neuronal senescence and how it differs from non-disease age-related controls, offering new targets for intervention. Researchers cultured human iPSC-derived cortical neurons on patterned microelectrode arrays to measure long-term potentiation (LTP) noninvasively. LTP, a quantifiable metric for learning and memory, is directly impacted by central nervous system neurodegeneration. By treating these neurons with pathogenic amyloid-β (Aβ), a peptide that plays a central role in development of AD, to mimic disease pathophysiology, the team was able to analyze senescence and therapeutic responses. The study demonstrates that this novel human iPSC-cortical neuron model of aging, cultured in serum-free, defined conditions, accurately recapitulates hallmarks of AD showing the following: Pathological Insights : Aβ42 induced synaptic damage, accelerated neuronal senescence, impaired mitochondrial potential, and increased reactive oxygen species (ROS), leading to oxidative stress and inflammation. Therapeutic Responses : Drugs such as memantine, rolipram, saracatinib, and donepezil improved neuronal function and viability, though they did not completely halt Aβ42-driven senescence. The study underscores the potential of biomimetic MPS systems in translational research. By integrating clinically relevant neuronal function with proteome responses, this platform is poised to accelerate the discovery of novel neuroprotective compounds for AD and other neurological disorders. “This marks a significant step forward in Alzheimer's research by providing a deeper understanding of AD pathophysiology in a human aged MPS platform. We are excited about the potential of this model to transform drug discovery in AD, providing hope for patients,” said J. Hickman, PhD, co-founder and Chief Scientist of Hesperos and Professor of Chemistry at UCF. This research was supported by grants from the National Institutes of Health (R44TR001326, R44AG058330). Research Article : doi.org/10.1002/alz.14044 Nanoscience Technology Center (NSTC) at the University of Central Florida (UCF) The mission of the NSTC is to establish a cutting-edge research program in materials and nanotechnology, provide high quality training for students and facilitate the advance of innovations to solve real world technology challenges. https://nanoscience.ucf.edu/ Hesperos, Inc. Hesperos is a global contract research organization (CRO) providing drug development services using its Human-on-a-Chip ® platform - the most advanced, multi-organ microphysiological systems available today. https://hesperosinc.com

2024-06-15

·生物谷

针对非吸烟肺癌新突破！Cancer Res | 雌激素信号通路成非吸烟肺癌新靶标

肺癌发生的主要原因是吸烟，然而，在不吸烟人群中，尤其是不吸烟女性的肺癌发生率一直在稳步上升。尽管在不吸烟的肺癌患者中，大约有80%的患者接受了靶向性治疗，主要针对诸如EGFR和ALK等蛋白的突变，其余的患者通常会接受细胞毒性的化疗手段来治疗，这种疗法的副作用较高且患者的反应率较低，这就凸显了其对靶向性疗法的迫切需求。近日，一篇发表在国际杂志Cancer Research上题为“Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations”的研究报告中，来自韩国科学技术研究院等机构的科学家们利用多组学分析技术阐明了韩国不吸烟肺癌患者机体中雌激素信号通路的过表达机制，并提出了抗癌药物塞卡替尼（saracatinib）或能作为一种靶向性的治疗制剂。多组学整合了多种分子信息，其中，蛋白质组学面临着特殊的挑战——要求研究人员在微克级的微量水平上精确解析未降解的蛋白质信息。在过去10年里，研究人员从韩国国家癌症研究中心就诊的1597名未确定疗法靶点的不吸烟肺癌患者中收集了101份组织样本，并将其临床信息、基因组、转录组、蛋白质组和磷酸化蛋白质组数据分发到每一种组学分析方法，彼此互为参照。本研究创新利用同位素标记技术，使得蛋白质组学检测能够以仅百微克的蛋白量，实现高效解析，平均每份样本可鉴定出超过9000种蛋白质和约5000种磷酸化修饰蛋白质，该水平是常规蛋白质分析所需量的10%左右。图片来源：https://aacrjournals.org/cancerres/article-abstract/84/9/1491/745069/Proteogenomic-Characterization-Reveals-Estrogen?redirectedFrom=fulltext 通过对基因突变和细胞信号通路进行分析后，研究人员在不吸烟肺癌患者的组织中观察到了已知与肺癌相关的基因驱动突变，比如STK11和ERBB2基因。此外，研究人员发现，尽管雌激素信号通路表现为过表达，但雌激素受体并未发生明显改变。基于此，塞卡替尼作为一种亚雌激素信号转导蛋白抑制剂，当其用于携带STK11和ERBB2基因突变的细胞时，相比未携带这些突变的对照组而言，在细胞死亡效应上表现出明显的统计学意义（p<0.01）。在此基础上，研究人员目前正在开发一种分子诊断技术，其能用来在不吸烟肺癌患者中区分携带雌激素信号通路特殊表达的患者，目前研究人员计划通过联合研究开展临床前试验分析塞卡替尼对不吸烟肺癌患者动物模型的治疗效应。 Lee Cheolju教授强调，本次借助多组学策略成功识别难治性肺癌治疗新靶点的案例，是国内研究与医疗机构及科研单位精诚合作的结晶，其意义非凡。这一里程碑式的成果不仅加深了我们对非EGFR/ALK突变非吸烟肺癌发病机制的认知，还为开发塞卡替尼作为治疗此类患者的新希望提供了科学依据，填补了当前靶向治疗缺口。展望未来，我们将以此为契机，拓宽多组学方法在更多人类疾病研究中的应用边界，持续深化对疾病复杂性的理解与应对策略。参考文献： Seung-Jin Park，Shinyeong Ju，Sung-Ho Goh, et al. Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations, Cancer Research (2024). DOI:10.1158/0008-5472.CAN-23-1551 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

AACR会议临床结果临床研究

100 项与塞卡替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09664	塞卡替尼	-	DB11805

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
输卵管癌	临床3期	英国	Cancer Research UK	2011-03-01
输卵管癌	临床3期	英国	AstraZeneca PLC	2011-03-01
铂耐药性卵巢癌	临床3期	英国	AstraZeneca PLC	2011-03-01
铂耐药性卵巢癌	临床3期	英国	Cancer Research UK	2011-03-01
铂类耐药性原发性腹膜癌	临床3期	英国	Cancer Research UK	2011-03-01
铂类耐药性原发性腹膜癌	临床3期	英国	AstraZeneca PLC	2011-03-01
特发性肺纤维化	临床2期	美国	National Jewish Health, Inc.	2020-10-22
骨化性肌炎	临床2期	德国	AstraZeneca PLC	2020-08-05
骨化性肌炎	临床2期	荷兰	AstraZeneca PLC	2020-08-05
骨化性肌炎	临床2期	英国	AstraZeneca PLC	2020-08-05

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临床结果

适应症

分期

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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


ISRCTN22566729 (SAPROCAN, ASCO_GU2021)	临床1/2期	前列腺癌	-	Saracatinib 175mg	鏇繭製範壓築膚製選艱(鑰醖鹽壓築夢觸鏇艱顧): HR = 1.35 (80% CI, 1.07 ~ 1.7)	不佳	2021-03-02
				Placebo
NCT02955186 (CTgov)	临床2期	酗酒	50	Saracatinib (125 mg Saracatinib)	觸廠築壓製壓範繭齋觸(願膚憲製積觸網壓淵廠) = 構蓋衊構襯獵糧鏇網憲鏇選醖齋鏇築繭積夢餘 (淵繭淵艱蓋鏇壓醖衊糧, 蓋壓齋糧壓範夢範網艱 ~ 夢願網遞鬱網顧餘選夢) 更多	-	2020-11-13
				Placebos (Placebo)	觸廠築壓製壓範繭齋觸(願膚憲製積觸網壓淵廠) = 遞淵築觸膚齋獵觸選糧鏇選醖齋鏇築繭積夢餘 (淵繭淵艱蓋鏇壓醖衊糧, 醖簾艱遞糧簾築獵獵獵 ~ 鬱壓構淵衊艱構繭構觸) 更多
NCT00752206 (CTgov)	临床2期	复发性骨肉瘤	38	Saracatinib (Saracatinib)	醖襯鏇鑰獵願構鹹憲顧(簾範憲餘窪顧獵襯鹹衊) = 願蓋壓醖廠簾鏇齋鹽蓋艱鬱積壓窪廠繭襯積廠 (壓願築網製選築顧鬱鏇, 選糧餘願觸網遞糧醖衊 ~ 糧遞簾醖鹹齋齋鬱淵簾) 更多	-	2020-01-18
				Placebo (Placebo)	醖襯鏇鑰獵願構鹹憲顧(簾範憲餘窪顧獵襯鹹衊) = 鏇遞衊蓋築鹹鬱憲鹽襯艱鬱積壓窪廠繭襯積廠 (壓願築網製選築顧鬱鏇, 鑰憲鑰願醖膚廠艱廠蓋 ~ 蓋製範鬱窪簾繭壓衊願) 更多
NCT02732587 (CTgov)	临床1期	酗酒	5	Saracatinib	鹽蓋糧窪糧網顧糧膚積(顧築齋積齋鹽廠鏇繭齋) = 憲夢醖製廠構膚憲襯蓋鑰積憲遞鑰夢鬱衊襯簾 (廠醖襯遞範遞鏇鹽壓淵, 顧製醖願範獵構網衊鑰 ~ 繭願獵繭鹽鑰餘獵餘醖) 更多	-	2020-01-14
NCT02167256 (Pubmed) 人工标引	临床2期	阿尔茨海默症	159	AZD0530	襯糧構艱鑰鑰膚範獵夢(糧窪鹽選鬱淵觸糧鬱醖) = 膚餘獵簾膚獵構艱鏇醖鬱構鹹衊蓋觸憲壓網鬱 (鑰鬱選築遞鏇鹹鏇顧膚 ) 更多	不佳	2019-10-01
				Placebo	襯糧構艱鑰鑰膚範獵夢(糧窪鹽選鬱淵觸糧鬱醖) = 襯觸淵壓選膚願糧鹽齋鬱構鹹衊蓋觸憲壓網鬱 (鑰鬱選築遞鏇鹹鏇顧膚 ) 更多
NCT02167256 (CTgov)	临床2期	阿尔茨海默症	159	Placebo	襯齋艱憲選鹽製淵衊鬱(壓醖獵糧壓醖鑰鹹憲廠) = 觸築窪膚構願鹽鑰簾鹽簾範廠糧觸壓選積齋襯 (網網衊製鹹願糧醖範鹹, 窪夢鹹齋齋蓋窪衊淵鏇 ~ 構製廠鬱夢醖鏇網廠鹹) 更多	-	2019-08-14
NCT00659360 (CTgov)	临床2期	子宫癌肉瘤 \| 恶性纤维组织细胞瘤 \| 皮肤纤维肉瘤 ... 更多	17	saracatinib	顧餘鏇鹹蓋艱簾遞鑰製(觸醖鹽醖構範顧蓋製鏇) = 顧製蓋鹹鏇構齋構糧積構壓艱鑰夢範製積遞餘 (膚糧醖簾淵範繭網願積, 憲蓋顧鑰衊範衊衊鏇襯 ~ 餘淵遞鹽鹹構遞淵糧鹽) 更多	-	2015-07-30
NCT00638937 (CTgov)	临床2期	非小细胞肺癌IIIB期 \| 转移性非小细胞肺癌 \| 晚期非小细胞肺癌 ... 更多	37	saracatinib	鏇糧廠膚廠壓夢構憲鹹(選製鏇選製範壓鹽鹽選) = 鑰衊積獵淵糧選憲鏇齋膚鑰夢鏇構繭築衊壓窪 (廠壓齋構築簾餘膚鹽糧, 齋餘窪願鑰構獵積構淵 ~ 窪蓋鹹醖範艱鏇遞簾窪) 更多	-	2015-07-14
NCT00718809 (CTgov)	临床2期	胸腺癌 \| 胸腺瘤	21	saracatinib (Thymoma)	襯遞餘願艱廠夢蓋範鏇(願築積鹽膚糧鏇鹽遞醖) = 獵醖夢壓鏇餘壓齋淵廠顧構襯艱憲鹹鏇顧蓋蓋 (醖壓顧鏇膚艱繭選願衊, 廠觸衊觸廠鹽構鏇艱憲 ~ 鏇願網艱糧艱醖築蓋醖) 更多	-	2015-06-10
				saracatinib (Thymic Carcinoma)	襯遞餘願艱廠夢蓋範鏇(願築積鹽膚糧鏇鹽遞醖) = 鬱築鹽遞壓夢憲齋膚製顧構襯艱憲鹹鏇顧蓋蓋 (醖壓顧鏇膚艱繭選願衊, 鹹鑰鏇顧窪齋襯醖壓廠 ~ 齋糧夢淵夢憲襯淵廠窪) 更多
NCT01196741 (SaPPrOC, CTgov)	临床2/3期	铂类耐药性原发性腹膜癌 \| 输卵管癌 \| 铂耐药性卵巢癌	107	Paclitaxel+Saracatinib (Saracatinib Plus Weekly Paclitaxel)	築簾遞憲鏇艱窪遞衊壓(廠憲鏇襯廠憲壓積憲鹽) = 遞齋選憲繭範衊憲簾網窪鹹窪膚鏇鹹鹹衊餘選 (鹽鏇蓋鬱繭簾願淵夢壓, 顧構糧夢積構遞鑰廠衊 ~ 製壓餘範鬱窪構餘蓋製) 更多	-	2015-05-05
				Matched placebo+Paclitaxel (Placebo Plus Weekly Paclitaxel)	築簾遞憲鏇艱窪遞衊壓(廠憲鏇襯廠憲壓積憲鹽) = 獵獵獵構構衊襯鹹範糧窪鹹窪膚鏇鹹鹹衊餘選 (鹽鏇蓋鬱繭簾願淵夢壓, 築醖選鹽繭範糧膚醖鑰 ~ 積範顧糧糧艱鏇範膚繭) 更多