泰西伐替尼(Tesevatinib) - 药物靶点：EGFR x HER2 x HER3 x HER4 x SRC family x VEGFR_专利_临床

概要

基本信息

药物类型

自体CAR-T

别名

Tesevatinib (USAN/INN)

+ [2]

靶点

EGFR x HER2 x HER3 x HER4 x SRC family x VEGFR

作用方式

拮抗剂、抑制剂

作用机制

EGFR拮抗剂(表皮生长因子受体erbB1拮抗剂)、HER2拮抗剂(受体蛋白酪氨酸激酶 erbB-2拮抗剂)、HER3拮抗剂(受体酪氨酸蛋白激酶erbB-3拮抗剂)

+ [3]

治疗领域

肿瘤呼吸系统疾病神经系统疾病+ [4]

在研适应症-

非在研适应症

晚期恶性实体瘤脑转移瘤乳腺癌+ [6]

原研机构

Exelixis, Inc.

在研机构-

非在研机构

Kadmon Corp. LLC

Exelixis, Inc.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构/序列

分子式C24H25Cl2FN4O2

InChIKeyHVXKQKFEHMGHSL-QKDCVEJESA-N

CAS号781613-23-8

关联

14

项与泰西伐替尼相关的临床试验

NCT03203642

/ Completed临床2期

A Double-blind Randomized Parallel Group Study of the Efficacy and Safety of Tesevatinib in Subjects With Autosomal Dominant Polycystic Kidney Disease

The goal of the study was to compare and evaluate safety and efficacy of tesevatinib 50 milligrams (mg) versus placebo in participants with autosomal dominant polycystic kidney disease (ADPKD).

开始日期2017-10-12

申办/合作机构

Kadmon Holdings, Inc.

NCT03096080

/ Completed临床1期

A Phase 1, Safety, Pharmacokinetic, Single Ascending Dose Study of Tesevatinib in Pediatric Subjects With Autosomal Recessive Polycystic Kidney Disease (ARPKD)

This study evaluates safety and tolerability of a single ascending dose of a tesevatinib liquid formulation administered to pediatric subjects with ARPKD.

开始日期2017-08-24

申办/合作机构

Kadmon Corp. LLC

NCT02844439

/ Completed临床2期

A Phase 2, Multicenter Study of Tesevatinib Monotherapy in Patients With Recurrent Glioblastoma

This is a multicenter, Phase 2 study to assess the activity of tesevatinib in patients with recurrent glioblastoma.

开始日期2016-06-01

申办/合作机构

Kadmon Corp. LLC

100 项与泰西伐替尼相关的临床结果

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100 项与泰西伐替尼相关的转化医学

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100 项与泰西伐替尼相关的专利（医药）

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41

项与泰西伐替尼相关的文献（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.

2024-07-01·Journal of Biological Chemistry

Crosstalk of MAP3K1 and EGFR signaling mediates gene-environment interactions that block developmental tissue closure

Article

作者: Xia, Ying ; Medvedovic, Mario ; Kimura, Eiki ; Mongan, Maureen ; Xiao, Bo ; Hsu, Wei-Wen ; Puga, Alvaro ; Wang, Jingjing

Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure that is dependent on the mitogen-activated protein kinase kinase kinase 1 (MAP3K1). Map3k1 KO in mice results in defective eyelid closure and an autosomal recessive eye-open at birth phenotype. We have shown that in utero exposure to dioxin, a persistent environmental toxicant, induces the same eye defect in Map3k1^+/- heterozygous but not WT pups. Here, we explore the mechanisms of the Map3k1 (gene) and dioxin (environment) interactions (GxE) underlying defective eyelid closure. We show that, acting through the aryl hydrocarbon receptor, dioxin activates epidermal growth factor receptor signaling, which in turn depresses MAP3K1-dependent Jun N-terminal kinase (JNK) activity. The dioxin-mediated JNK repression is moderate but is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1^+/- embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1^+/- pups, whereas knockout of Jnk1 and S1pr that encodes the sphigosin-1-phosphate (S1P) receptors upstream of the MAP3K1-JNK pathway potentiates the dioxin toxicity. Our novel findings show that the crosstalk of aryl hydrocarbon receptor, epidermal growth factor receptor, and S1P-MAP3K1-JNK pathways determines the outcome of dioxin exposure. Thus, gene mutations targeting these pathways are potential risk factors for the toxicity of environmental chemicals.

2024-02-01·Journal of Mathematical Chemistry

Identification of potential oral cancer drugs as Bcl-2 inhibitors from known anti-neoplastic agents through docking studies

作者: Pal, Debnath ; Raychaudhury, Chandan ; Srinivasan, Shreyaa

Oral Cancer is one of the major killers in India and of global concern.An attempt has been made here to identify small mol. inhibitors of Bcl-2 (B-cell lymphoma 2) protein through docking studies in search of new oral cancer drugs from a curated set of 276 known anti-neoplastic agents obtained from PubChem.The Bcl-2 protein (PDB id:6QGH), being complexed with ligand ABT-263, has been detached from the complex.The ligand-free protein and 276 compounds have been prepared for docking studies using corresponding tools available in Discovery Studio (DS), ver.4.1.The 276 compounds have been docked on the first site of the protein using LibDock docking program available in DS.By considering Methotrexate as the reference compound (LibDock score: 114.76), we have identified 25 compounds as the most potential oral cancer drugs having LibDock scores greater than 100.Another set of 114 compounds with LibDock scores between 80 and 100 have also been identified as the next set of potential drug candidates and some of them show anti-apoptosis properties.Two other compounds with LibDock scores below 80 have been identified for comparative analyses with some high-scoring compoundsThe docking results have been given in tables and pictures (screenshots) of the docked poses of selected compounds have been shown to illustrate the findings.Finally, the most suitable potential compounds have been identified by applying Lipinski′s Rule of 5.The present approach using known anti-neoplastic agents is believed to help discover potential anti-oral cancer drug candidates.

100 项与泰西伐替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11772	泰西伐替尼	-	DB11973

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
常染色体隐性遗传性多囊肾	临床3期	美国	Kadmon Corp. LLC	2017-08-24
复发性胶质母细胞瘤	临床3期	美国	Kadmon Corp. LLC	2016-06-01
常染色体显性多囊肾病	临床3期	美国	Kadmon Corp. LLC	2015-12-25
脑转移瘤	临床3期	美国	Kadmon Corp. LLC	2015-11-01
软脑膜转移性恶性肿瘤	临床3期	美国	Kadmon Corp. LLC	2015-11-01
非小细胞肺癌IIIB期	临床3期	美国	Kadmon Corp. LLC	2011-12-14
乳腺癌	临床3期	美国	Exelixis, Inc.	2008-06-01
非小细胞肺癌	临床3期	美国	Exelixis, Inc.	2008-06-01
晚期恶性实体瘤	临床3期	美国	Kadmon Corp. LLC	2006-07-01

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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


NCT03203642 (CTgov)	临床2期	常染色体显性多囊肾病	80	Tesevatinib (Tesevatinib)	構築觸夢膚憲膚願製範(獵膚鹹壓壓築製淵鏇觸) = 網築鹹簾範襯繭網蓋構憲膚夢築鹹願鏇鬱顧鹹 (範膚憲鹹淵鑰鬱網餘願, 餘選壓襯艱積簾繭鹹糧 ~ 襯廠範憲襯鹽遞製醖襯) 更多	-	2023-02-06
NCT03203642 (CTgov)	临床2期	常染色体显性多囊肾病	80	Placebo (Placebo)	構築觸夢膚憲膚願製範(獵膚鹹壓壓築製淵鏇觸) = 壓壓膚築齋鹽鑰齋鏇遞憲膚夢築鹹願鏇鬱顧鹹 (範膚憲鹹淵鑰鬱網餘願, 鏇觸糧窪襯簾範窪鏇餘 ~ 簾膚齋衊壓壓範憲簾鹽) 更多	-	2023-02-06
NCT01559363 (CTgov)	临床1/2期	常染色体显性多囊肾病	69	Tesevatinib (Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing)	(積範網襯簾觸構顧艱糧) = 蓋衊窪顧鏇窪網觸構鑰鬱鹽觸繭鑰鏇衊獵窪窪 (積觸構製蓋齋製獵鬱顧, 簾鏇蓋鬱顧衊糧構廠範 ~ 遞鑰齋顧鏇膚鹹積齋繭) 更多	-	2022-11-08
NCT01559363 (CTgov)	临床1/2期	常染色体显性多囊肾病	69	Tesevatinib (Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing)	(積範網襯簾觸構顧艱糧) = 鏇獵齋選遞齋壓淵醖鏇鬱鹽觸繭鑰鏇衊獵窪窪 (積觸構製蓋齋製獵鬱顧, 簾夢膚選襯獵衊觸壓艱 ~ 窪築餘廠積壓獵鑰製廠) 更多	-	2022-11-08
KD019-101 \| SILK (ASN2019)	临床1/2期	常染色体显性多囊肾病	13	Tesevatinib 50 mg QD	遞積網鏇鏇襯齋繭繭網(壓夢願餘鬱壓積糧壓製) = Grade 3 AEs were reported in 3 patients (CHF, HTN, and Herpes zoster) and were considered unlikely or unrelated to study drug 顧蓋顧範構蓋蓋壓鹹廠 (願鹹鑰簾窪艱鏇蓋獵鹹 ) 更多	积极	2019-11-05
ASN2016	N/A	多囊肾	24	Tesevatinib 50 mg	廠繭蓋簾製襯壓餘顧艱(膚夢鑰築遞蓋夢窪製鏇) = 糧淵鏇齋願衊網鏇構壓築鬱糧齋鹽網選鏇淵製 (鬱壓夢廠襯築願築齋觸 ) 更多	积极	2016-11-15
NCT02154529 (ASCO2016)	临床1/2期	HER2阳性转移性乳腺癌	8	Tesevatinib 300 mg QD	(夢構鬱餘製鹹簾獵鏇餘) = Grade 3 diarrhea and Grade 3 QTc prolongation 膚淵積襯鬱範構獵繭壓 (簾繭壓鹹憲網範鬱簾繭 )	-	2016-05-20
NCT02154529 (ASCO2016)	临床1/2期	HER2阳性转移性乳腺癌	8	Tesevatinib 350 mg QD		-	2016-05-20
ASN2015	N/A	常染色体显性多囊肾病	46	Tesevatinib 150 mg/day	糧餘夢衊襯選鏇願築遞(夢遞鹽觸艱襯糧淵繭醖) = In oncology trials the most common adverse events (AEs) were EGFR inhibitor AEs of acneiform rash and diarrhea. 醖淵壓襯構網製鏇衊鹹 (網壓齋範壓獵製夢鹽鬱 ) 更多	不佳	2015-11-03
ASN2015	N/A	常染色体显性多囊肾病	46	Tesevatinib 100 mg/day		不佳	2015-11-03
ASCO2008	临床2期	非小细胞肺癌	41	XL647 350 mg (intermittent cohort)	齋醖鬱窪鏇遞鬱築鏇膚(廠鹹廠鏇廠廠遞獵淵顧) = 簾鑰獵蓋夢選獵淵範鏇艱蓋憲範醖鏇積夢鏇積 (鬱膚觸壓糧窪網積餘簾 ) 更多	-	2008-05-20
ASCO2008	临床1期	晚期恶性实体瘤	31	XL647	(醖積觸顧顧廠構選夢鏇) = 構鹽鏇築憲壓簾壓廠築構襯艱構觸窪鬱構窪鬱 (網窪鑰壓觸鏇廠襯鬱齋 )	-	2008-05-20
ASCO2007	临床1期	晚期恶性实体瘤	-	XL647	(蓋築簾窪繭壓鹽獵憲積) = 遞繭築願襯遞選齋夢鹹鑰憲醖餘遞積顧顧餘鑰 (壓簾醖築積膚顧糧鏇窪 ) 更多	-	2007-06-20
ASCO2005	临床1期	晚期恶性实体瘤	12	XL647	(鹹觸簾夢網齋糧構齋觸) = 襯夢構壓壓膚積衊簾襯衊憲膚積網醖窪憲繭構 (顧構鹽鏇構夢蓋廠襯繭 ) 更多	-	2005-06-01