盐酸西莫替尼(Simotinib Hydrochloride) - 药物靶点：EGFR_在研适应症：非小细胞肺癌，乳腺癌，结肠癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Simotinib、Ximotini

+ [1]

靶点

EGFR

作用方式

拮抗剂

作用机制

EGFR拮抗剂(表皮生长因子受体erbB1拮抗剂)

治疗领域

肿瘤消化系统疾病呼吸系统疾病+ [1]

在研适应症

非小细胞肺癌乳腺癌结肠癌

非在研适应症-

原研机构

先聲藥業集團有限公司

在研机构

先聲藥業集團有限公司

Advenchen Laboratories LLC

江苏先声药物研究有限公司

+ [1]

非在研机构

江苏先声药业有限公司

权益机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)临床1期

特殊审评特殊审批 (中国)

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结构/序列

分子式C25H26ClFN4O4

InChIKeyOXWUWXCJDBRCCG-UHFFFAOYSA-N

CAS号944258-89-3

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关联

3

项与盐酸西莫替尼相关的临床试验

CTR20131337

/ Active, not recruiting临床1期

盐酸西莫替尼片在晚期NSCLC患者中连续给药安全性、耐受性、药动学Ib期临床试验

观察盐酸西莫替尼片的在晚期NSCLC患者中安全性和耐受性，确定该药在人体内的剂量限制性毒性（DLT）及最大耐受剂量（MTD）；揭示盐酸西莫替尼片的药代动力学特征；初步观察盐酸西莫替尼片的有效性和有效剂量。

开始日期2013-04-15

申办/合作机构

江苏先声药物研究有限公司

[+1]

NCT01772732

/ Unknown status临床1期

Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Simotinib Hydrochloride in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.

开始日期2012-12-01

申办/合作机构

江苏先声药业有限公司

NCT01469910

/ Completed临床1期

Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Simotinib Hydrochloride in Healthy Subjects

The purpose of this study is to assess the safety and pharmacokinetics of single ascending doses of Simotinib Hydrochloride in healthy subjects.

开始日期2011-09-01

申办/合作机构

江苏先声药业有限公司

100 项与盐酸西莫替尼相关的临床结果

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100 项与盐酸西莫替尼相关的转化医学

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100 项与盐酸西莫替尼相关的专利（医药）

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6

项与盐酸西莫替尼相关的文献（医药）

2024-09-05·Journal of Computational Chemistry

GraphEGFR: Multi‐task and transfer learning based on molecular graph attention mechanism and fingerprints improving inhibitor bioactivity prediction for EGFR family proteins on data scarcity

Article

作者: Kinchagawat, Jiramet ; Rungrotmongkol, Thanyada ; Prommin, Chanatkran ; Yamprasert, Nattawin ; Kaewnuratchadasorn, Pawit ; Boonyarit, Bundit ; Nutanong, Sarana

AbstractThe proteins within the human epidermal growth factor receptor (EGFR) family, members of the tyrosine kinase receptor family, play a pivotal role in the molecular mechanisms driving the development of various tumors. Tyrosine kinase inhibitors, key compounds in targeted therapy, encounter challenges in cancer treatment due to emerging drug resistance mutations. Consequently, machine learning has undergone significant evolution to address the challenges of cancer drug discovery related to EGFR family proteins. However, the application of deep learning in this area is hindered by inherent difficulties associated with small‐scale data, particularly the risk of overfitting. Moreover, the design of a model architecture that facilitates learning through multi‐task and transfer learning, coupled with appropriate molecular representation, poses substantial challenges. In this study, we introduce GraphEGFR, a deep learning regression model designed to enhance molecular representation and model architecture for predicting the bioactivity of inhibitors against both wild‐type and mutant EGFR family proteins. GraphEGFR integrates a graph attention mechanism for molecular graphs with deep and convolutional neural networks for molecular fingerprints. We observed that GraphEGFR models employing multi‐task and transfer learning strategies generally achieve predictive performance comparable to existing competitive methods. The integration of molecular graphs and fingerprints adeptly captures relationships between atoms and enables both global and local pattern recognition. We further validated potential multi‐targeted inhibitors for wild‐type and mutant HER1 kinases, exploring key amino acid residues through molecular dynamics simulations to understand molecular interactions. This predictive model offers a robust strategy that could significantly contribute to overcoming the challenges of developing deep learning models for drug discovery with limited data and exploring new frontiers in multi‐targeted kinase drug discovery for EGFR family proteins.

2016-04-01·Anti-Cancer Drugs4区 · 医学

Simotinib as a modulator of P-glycoprotein

4区 · 医学

Article

作者: Chen, Yanfen ; Zhu, Qubo ; Huang, Lingling ; Shen, Cheng ; Cheng, Zeneng ; Yan, Huiwen

As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug-drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high-performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment.

2014-02-01·Analytical and Bioanalytical Chemistry

Development and validation of a UPLC–MS/MS assay for the quantification of simotinib in human plasma

Article

作者: Ping Du ; Yuankai Shi ; Xiaohong Han ; Sheng Yang ; Yuanyuan Song ; Xingsheng Hu ; Ning Li

Simotinib is a novel oral small-molecule tyrosine kinase inhibitor that has demonstrated equal or superior antineoplastic activities to erlotinib in preclinical studies. In support of a clinical pharmacokinetic study, a sensitive and accurate liquid chromatography (LC) method with mass spectrometry detection using multiple reaction monitoring (MRM) in positive ion mode was developed and validated for the quantification of simotinib in human plasma. The sample preparation procedure involved a simple protein precipitation with methanol. Erlotinib was used as the internal standard. The optimal chromatographic behavior was achieved on a Zorbax SB-C8 column (2.1 mm × 100 mm, 3.5 μm) using a mixture of 0.1% formic acid with 10 mM ammonium formate/methanol (20:80, v/v) as the mobile phase. The total LC analysis time per injection was 4 min with a flow rate of 0.2 mL/min. The recovery was greater than 90% and no significant matrix effect was observed. The assay was validated over the concentration range of 1-1,000 ng/mL. The intra- and interday precision and accuracy of the quality control samples at low, medium, and high concentration levels showed at most 9.4% relative standard deviation (RSD) and -7.4 to 7.4% relative errors (RE). Assay selectivity, freeze/thaw stability, storage stability, and dilution effects were also assessed. The method is now used to support clinical pharmacokinetic studies in patients with non-small cell lung cancer (NSCLC) after oral administration of simotinib.

100 项与盐酸西莫替尼相关的药物交易

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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
非小细胞肺癌	临床1期	中国	先声药业有限公司	2013-04-15
非小细胞肺癌	临床1期	中国	江苏先声药物研究有限公司	2013-04-15
乳腺癌	临床1期	-	Advenchen Laboratories LLC	-
乳腺癌	临床1期	中国	先聲藥業集團有限公司	-
结肠癌	临床1期	中国	先聲藥業集團有限公司	-
结肠癌	临床1期	-	Advenchen Laboratories LLC	-

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临床结果

适应症

分期

评价

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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


NCT01772732 (Pubmed \| Cancer Manag Res) 人工标引	临床1期	EGFR突变的非小细胞肺癌 EGFR Mutation	41	simotinib	(簾膚壓鑰壓艱廠衊範鹽) = 構艱夢鹽餘積築齋願鹽積鬱製鏇衊觸齋窪齋齋 (夢窪鹹製憲範獵淵膚餘 ) 更多	积极	2019-05-13
NCT01772732 (ASCO2017)	临床1期	晚期非小细胞肺癌一线	41	Simotinib	(願製積淵簾淵網願鹽構) = Simotinib was well tolerated, with encouraging efficacy observed in NSCLC patients with EGFR sensitive mutations, particularly in those with BM 窪鹽淵艱憲膚醖繭衊範 (遞憲遞壓艱鹹憲鏇選顧 )	-	2017-05-30