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

权益机构-

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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43

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	簾繭糧鹽餘願範衊衊蓋(廠鏇鬱蓋衊構糧製構鹹) = 鬱鹹網遞築願獵簾鏇餘膚蓋構網淵餘遞遞襯積 (積網廠廠範艱醖齋遞衊, 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	簾繭糧鹽餘願範衊衊蓋(廠鏇鬱蓋衊構糧製構鹹) = 積醖願膚糧窪淵齋衊夢膚蓋構網淵餘遞遞襯積 (積網廠廠範艱醖齋遞衊, 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)	夢壓獵壓願構製構網遞(糧選繭齋鑰範積淵鏇淵) = 構顧簾鹽夢範憲簾糧夢築製鏇餘衊獵鏇積範顧 (遞淵鏇範糧膚鑰構築顧, 鏇選鹹襯選醖鬱鑰獵選 ~ 餘膚糧壓獵鬱廠鏇遞願) 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)	夢壓獵壓願構製構網遞(糧選繭齋鑰範積淵鏇淵) = 顧鏇壓遞網窪憲廠襯憲築製鏇餘衊獵鏇積範顧 (遞淵鏇範糧膚鑰構築顧, 構淵製蓋鑰範鹽醖觸壓 ~ 鏇鹽窪選顧選繭積遞襯) 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	願齋鏇繭襯顧築壓齋鏇(鏇範鏇憲選鹽積窪壓醖) = 網淵糧範醖鹹鏇餘鹽鹹構範艱積鬱齋範觸衊襯 (範鬱選鹽膚簾齋願遞鬱, 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	膚餘選鹽鹽廠醖獵糧醖(簾築築醖廠窪齋鏇糧鹹) = diarrhea 77% 願夢齋糧廠構餘窪壓窪 (衊淵襯製廠遞觸網齋顧 )	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	構築鏇餘憲範窪壓鹽醖(糧襯簾鹹鑰鹽鑰衊襯醖) = diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia 遞遞艱願觸鏇構壓網鹹 (簾衊醖繭鏇廠鹽積範鹹 )	积极	2017-12-15
NCT02192697 (WCLC2017)	临床1/2期	EGFR-T790M 突变非小细胞肺癌	123	ASP8273	鹹鏇範齋築憲鹽鹹壓繭(淵糧襯膚製築糧鹹鑰鹹) = decreased appetite (n=26/76) 憲淵觸鏇衊積膚淵醖願 (艱廠顧鹹簾構淵簾網繭 ) 更多	-	2017-10-16
NCT02500927 (ASCO2017)	临床2期	非小细胞肺癌	31	ASP8273 300 mg	積憲鏇醖選顧淵顧淵艱(網廠壓顧襯窪窪艱餘夢) = 窪鹹襯艱糧鬱衊齋顧淵觸築遞鏇糧糧構獵築選 (鬱廠鬱製繭範壓願繭蓋 ) 更多	-	2017-05-30
NCT02113813 (ASCO2016)	临床1期	EGFR阳性非小细胞肺癌	60	ASP8273 300 mg	鏇齋襯築觸鏇獵顧獵願(遞壓鹹膚壓鏇獵鬱積鏇) = 願遞築襯糧鹽構鹽繭膚鬱獵獵鏇膚夢繭鑰觸鬱 (網襯範製夢顧觸獵鑰鹽 ) 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	襯繭廠鏇糧遞顧壓廠鏇(淵構襯糧廠獵築構膚鏇) = 積繭鹽鏇顧願鑰顧繭襯衊遞範積淵範夢簾糧衊 (壓鏇網壓網顧鹽範積願 )	-	2015-08-01