Naquotinib(Naquotinib) - 药物靶点：EGFR T790M_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Naquotinib (USAN/INN)、Naquotinib Mesylate、ASP-8273

+ [1]

靶点

EGFR T790M

作用方式

抑制剂

作用机制

EGFR T790M抑制剂(表皮生长因子受体T790M抑制剂)

治疗领域

肿瘤呼吸系统疾病消化系统疾病

在研适应症-

非在研适应症

非小细胞肺癌非小细胞肺癌IIIB期胃癌

原研机构

Astellas Pharma, Inc.

在研机构-

非在研机构

Astellas Pharma Global Development, Inc.

Astellas Pharma, Inc.

安斯泰来制药（中国）有限公司

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)终止

特殊审评-

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结构/序列

分子式C31H46N8O6S

InChIKeyALDUQYYVQWGTMR-GJFSDDNBSA-N

CAS号1448237-05-5

关联

8

项与 Naquotinib 相关的临床试验

NCT03082300

/ Terminated临床1期

A Phase 1, Randomized, 2-period Crossover Study to Assess Bioequivalence of a Tablet Formulation Versus a Capsule Formulation of ASP8273 in Subjects With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations

The objective of this study is to evaluate the bioequivalence of a tablet formulation versus a capsule formulation of ASP8273 following a single dose under fasted condition in subjects with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. The study will also evaluate the safety and tolerability of a tablet formulation as a single dose and a capsule formulation as a single and multiple dose of ASP8273 in subjects with NSCLC harboring EGFR mutations.

开始日期2017-03-24

申办/合作机构

Astellas Pharma Global Development, Inc.

NCT03042013

/ Withdrawn临床2期

An Open-label, Multicenter, Rollover Study for Subjects Who Are Participating in an Astellas-sponsored ASP8273 Study

The purpose of the study is to evaluate long-term safety and tolerability of continuous treatment with ASP8273 in subjects who are participating in an Astellas-sponsored ASP8273 study which has completed, at a minimum, the primary analysis or have completed the individual study evaluation period and for whom the investigator feels the subject may have potential to continue to derive clinical benefit from treatment with ASP8273.

开始日期2017-02-28

申办/合作机构

Astellas Pharma Global Development, Inc.

NCT02674555

/ Withdrawn临床1期

A Phase 1 Study to Investigate the Absorption, Metabolism and Excretion of [14C]ASP8273 in Subjects With Solid Tumors Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

This is a study to investigate the absorption, metabolism and excretion of [14C] labeled ASP8273 in subjects with solid tumors harboring EGFR mutations (per local testing). This study consists of two parts (A and B).

开始日期2016-11-15

申办/合作机构

Astellas Pharma Global Development, Inc.

100 项与 Naquotinib 相关的临床结果

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100 项与 Naquotinib 相关的转化医学

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100 项与 Naquotinib 相关的专利（医药）

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42

项与 Naquotinib 相关的文献（医药）

2025-01-01·Journal of Cancer

Third generation vs first generation EGFR-TKIs in the first line treatment for EGFR-mutated locally advanced or metastatic non-small cell lung cancer: a meta-analysis based on randomized controlled trials

Article

作者: Zhang, Wenxiong ; Lin, Xueying ; Chen, Yuan ; Feng, Tanggui ; Qin, Yi ; Hu, Wenjie ; Dong, Taoming

Background: The prevailing belief is that third-generation tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) (TGET) outperform first-generation EGFR-TKIs (FGET) in managing advanced-stage EGFR-mutated non-small cell lung cancer (NSCLC). However, this standpoint lacks substantiation in evidence-based medicine. Therefore, this meta-analysis was conducted to compare the efficacy and adverse effects (AEs) of these two categories. Methods: We searched seven databases for relevant randomized controlled trials (RCTs), focusing on primary endpoints such as progression-free survival (PFS), overall survival (OS), and central nervous system PFS (CNS-PFS). Additional factors considered included treatment responses and AEs. Results: We analyzed 15 studies from 6 RCTs on six third-generation TKIs: Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Naquotinib, and Befotertinib. TGET showed better efficacy in PFS (hazard ratio [HR]: 0.55 [0.41, 0.75]), CNS-PFS (HR: 0.48 [0.35, 0.66]), CNS-objective response rate (CNS-ORR, risk ratio [RR]: 1.40 [1.19, 1.65]), and duration of response (DOR, HR: 0.52 [0.38, 0.72]). Most subgroups confirmed the PFS advantage. With longer survival time, the superiority in PFS, OS, and CNS-PFS of TGETs became more evident. Both groups had similar OS (HR: 0.86), ORR, CNS-DOR, total AEs, and grade 3-5 AEs. However, TGETs had more severe AEs (RR: 1.17 [1.02, 1.35]). Additionally, there were more grade 3-4 cases of diarrhea, decreased platelet count, pulmonary embolism, fatigue, decreased neutrophil count, and rash, and fewer grade 3-4 increases in alanine transaminase (ALT) and aspartate transaminase (AST) in the TGET group. The top 5 AEs in the TGET group were diarrhea (36.32%), rash (30.24%), decreased platelet count (29.15%), elevated serum creatinine (23.63%), and decreased white blood cell count (22.02%). Conclusions: Except for Naquotinib, TGETs demonstrate superiority over FGETs in treating EGFR-mutated locally advanced or metastatic NSCLC, showing improved survival and responses. However, the increased incidence of AEs necessitates careful consideration.

2024-11-05·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity

Article

作者: Eck, Michael J. ; Beyett, Tyler S. ; Rana, Jaimin K. ; Schaeffner, Ilse K. ; Zhao, Hanchen ; Jiang, Jie ; Santana, Jhasmer ; Jänne, Pasi A.

Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non–small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower K m, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

2024-02-01·Molecular pharmacology

A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology

Article

作者: Eck, Michael J ; Beyett, Tyler S ; Kim, Justin J ; Heppner, David E ; Jänne, Pasi A ; Schaeffner, Ilse K ; To, Ciric

Lung cancer is commonly caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric kinase inhibitors are unaffected by common ATP-site resistance mutations and represent a promising therapeutic strategy for targeting drug-resistant EGFR variants. However, allosteric inhibitors are antagonized by kinase dimerization, and understanding this phenomenon has been limited to cellular experiments. To facilitate the study of allosteric inhibitor pharmacology, we designed and purified a constitutive EGFR kinase dimer harboring the clinically relevant L858R/T790M mutations. Kinetic characterization revealed that the EGFR kinase dimer is more active than monomeric EGFR(L858R/T790M) kinase and has the same K_m,ATP Biochemical profiling of a large panel of ATP-competitive and allosteric EGFR inhibitors showed that allosteric inhibitor potency decreased by >500-fold in the kinase dimer compared with monomer, yielding IC₅₀ values that correlate well with Ba/F3 cellular potencies. Thus, this readily purifiable constitutive asymmetric EGFR kinase dimer represents an attractive tool for biochemical evaluation of EGFR inhibitor pharmacology, in particular for allosteric inhibitors. SIGNIFICANCE STATEMENT: Drugs targeting epidermal growth factor receptor (EGFR) kinase are commonly used to treat lung cancers but are affected by receptor dimerization. Here, we describe a locked kinase dimer that can be used to study EGFR inhibitor pharmacology.

100 项与 Naquotinib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10958	-	-	DB12036

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IIIB期	临床3期	美国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	日本	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	澳大利亚	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	比利时	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	加拿大	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	智利	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	法国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	德国	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	匈牙利	Astellas Pharma Global Development, Inc.	2016-02-11
非小细胞肺癌IIIB期	临床3期	意大利	Astellas Pharma Global Development, Inc.	2016-02-11

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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


NCT02588261 (Pubmed) 人工标引	临床3期	EGFR突变的非小细胞肺癌一线 EGFR Mutation	530	ASP8273	製淵鹽顧憲壓憲鹹繭艱(鑰膚鹹膚襯顧夢製齋鹽) = 簾築齋蓋範積積餘襯選選構繭夢廠築願構淵蓋 (糧夢願廠觸鬱築網憲簾, 5.6 ~ 11.1) 更多	不佳	2019-07-01
NCT02588261 (Pubmed) 人工标引	临床3期	EGFR突变的非小细胞肺癌一线 EGFR Mutation	530	gefitinib+erlotinib	製淵鹽顧憲壓憲鹹繭艱(鑰膚鹹膚襯顧夢製齋鹽) = 獵構顧鬱簾壓遞艱選顧選構繭夢廠築願構淵蓋 (糧夢願廠觸鬱築網憲簾, 8.8 ~ NE) 更多	不佳	2019-07-01
NCT02588261 (SOLAR, CTgov)	临床3期	非小细胞肺癌IIIB期	530	naquotinib mesilate (ASP8273)	齋鬱願願廠醖鏇觸鑰鬱(艱齋鬱鬱襯網網鏇選餘) = 醖願鹽齋積夢鏇獵夢膚網獵艱鏇觸網鹹鹹積構 (壓壓壓膚顧觸壓範淵廠, 廠簾鏇簾積簾遞廠構糧 ~ 獵鹹鏇襯蓋顧齋淵簾襯) 更多	-	2019-02-12
NCT02588261 (SOLAR, CTgov)	临床3期	非小细胞肺癌IIIB期	530	Erlotinib+Gefitinib (Erlotinib or Gefitinib)	齋鬱願願廠醖鏇觸鑰鬱(艱齋鬱鬱襯網網鏇選餘) = 淵構鏇構醖窪構網淵鹽網獵艱鏇觸網鹹鹹積構 (壓壓壓膚顧觸壓範淵廠, 選窪網獵廠鏇壓艱選積 ~ 簾積衊艱襯齋觸觸餘淵) 更多	-	2019-02-12
NCT02192697 (Pubmed \| Cancer Sci) 人工标引	临床1/2期	EGFR-T790M 突变非小细胞肺癌 EGFR Activation \| EGFR T790M Mutation	121	ASP8273	選積鹽積衊簾夢窪獵衊(齋構構廠鹹製選糧築糧) = 築鹽鑰衊廠願艱糧蓋糧糧觸顧膚襯範範夢構醖 (鏇襯範願窪顧積製淵遞, 30.9 ~ 54.0) 更多	积极	2018-09-01
NCT02500927 (Pubmed \| Cancer Sci) 人工标引	临床2期	EGFR阳性非小细胞肺癌 EGFR Mutation	31	ASP8273	齋壓憲淵鏇醖鹽築顧淵(鹹鏇壓襯窪積襯夢築衊) = diarrhea 77% 簾齋鑰蓋觸觸糧衊遞鏇 (顧糧遞鹽願襯糧範醖願 )	积极	2018-08-01
NCT02113813 (Pubmed) 人工标引	临床1期	EGFR突变的非小细胞肺癌 EGFR Mutation	110	ASP8273	齋顧簾鏇膚鏇選網廠選(選願獵壓廠壓範蓋構顧) = diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia 膚範構衊繭艱廠鑰夢淵 (繭齋鏇獵顧顧鹽蓋鏇鏇 )	积极	2017-12-15
NCT02192697 (WCLC2017)	临床1/2期	EGFR-T790M 突变非小细胞肺癌	123	ASP8273	蓋醖製鏇製廠遞範衊簾(齋鏇鑰淵衊製構鹽艱願) = decreased appetite (n=26/76) 觸壓廠範齋壓觸廠簾壓 (憲艱網鏇獵鬱簾遞憲艱 ) 更多	-	2017-10-16
NCT02500927 (ASCO2017)	临床2期	非小细胞肺癌	31	ASP8273 300 mg	壓餘醖廠憲壓糧淵糧鏇(壓製選蓋網鹽蓋鏇壓憲) = 構襯鏇醖願鹽願獵遞鹽醖顧鏇鹹廠艱糧築繭餘 (鏇網範膚選積獵觸鑰觸 ) 更多	-	2017-05-30
NCT02113813 (ASCO2016)	临床1期	EGFR阳性非小细胞肺癌	60	ASP8273 300 mg	廠願網壓遞鹹淵鏇構艱(願顧夢壓鹽獵衊廠鹹廠) = 壓鬱淵鹽齋襯鬱憲選願顧齋鬱繭襯襯選糧淵醖 (製餘膚製蓋鏇遞觸觸襯 ) 更多	积极	2016-05-20
NCT02192697 \| NCT02113813 (AACR2015)	临床1/2期	EGFR突变胶质母细胞瘤	-	ASP8273	膚淵鏇選選製餘鏇衊鹹(衊醖艱簾襯蓋積衊獵醖) = 簾積艱衊衊糧遞鏇蓋積構襯壓齋衊積顧築淵觸 (觸膚鬱廠構醖網觸壓製 )	-	2015-08-01