TAS-114(TAS-114) - 药物靶点：DPD x dUTPase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

DPD x dUTPase

作用机制

DPD抑制剂(二氢嘧啶脱氢酶抑制剂)、dUTPase抑制剂(dUTP焦磷酸酶抑制剂)

治疗领域

肿瘤呼吸系统疾病

在研适应症-

非在研适应症

晚期非小细胞肺癌晚期恶性实体瘤非小细胞肺癌

原研机构

Taiho Pharmaceutical Co., Ltd.

在研机构-

非在研机构

Taiho Oncology, Inc.

Taiho Pharmaceutical Co., Ltd.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

7

项与 TAS-114 相关的临床试验

JPRN-UMIN000028329 / Completed临床2期IIT

Phase II study of TAS-114 in combination with S-1 in patients with advanced gastric cancer refractory to prior chemotherpy. - TAS114_GC study

开始日期2017-10-17

申办/合作机构

National Cancer Center Hospital East

NCT02855125 / Completed临床2期

A Randomized, Open-Label, Multi-Center, International Phase 2 Study of TAS-114 in Combination With S-1 in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

This is a randomized, open-label, Phase 2 study of TAS-114 administered in combination with S-1, to investigate the efficacy, safety and tolerability of the TAS-114/S-1 regimen in patients with advanced or metastatic NSCLC.
The study will be conducted internationally in 2 regions: Asian [Japan] and Western [Europe and US]. Patients will be randomized into TAS-114/S-1 arm versus S-1 control arm in a 1:1 ratio.

开始日期2016-08-29

申办/合作机构

Taiho Oncology, Inc.

NCT02454062 / Completed临床1期

A Phase I, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability and Pharmacokinetic Study of TAS-114 in Combination With S-1 in Patients With Advanced Solid Tumors

A Phase I, Open-Label, International, Multicenter, Non-Randomized, Dose-Escalating Safety, Tolerance and Pharmacokinetic Study of Oral Administration of TAS-114 in Combination with S-1 in a Twice Daily Schedule for 14 Days in Patients with Advanced Solid Tumors.

开始日期2013-03-01

申办/合作机构

Taiho Oncology, Inc.

100 项与 TAS-114 相关的临床结果

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100 项与 TAS-114 相关的转化医学

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100 项与 TAS-114 相关的专利（医药）

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10

项与 TAS-114 相关的文献（医药）

2022-11-01·Cancer Letters

Overexpression of nucleotide metabolic enzyme DUT in hepatocellular carcinoma potentiates a therapeutic opportunity through targeting its dUTPase activity

Article

作者: Lo, Wing Sze ; Xu, Mingjing ; Wong, Nathalie ; You, Wenxing ; Liu, Yue ; Wan, Ho Lee ; Wong, Alissa M ; Ng, Kelvin K-C ; Ding, Xiaofan

Uracil misincorporation during DNA replication is a major cell toxic event, of which cancer cells overcome by activating the dUTPase enzyme. The DUT gene is the only known dUTPase in human. Despite reports on common upregulations in cancers, the role of DUT in human hepatocellular carcinoma (HCC) remains largely undetermined. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC tumors and correlated with advanced stage HCC. Knockout of DUT in HCC cell lines showed suppressed proliferation through cell cycle arrest and a spontaneous induction of DNA damage. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Transcriptome analysis highlighted the NF-κB survival signaling as the downstream effector pathway of DUT in overriding oxidative stress-induced cell death. Interestingly, stably expressed DUT in liver progenitor organoids conferred drug resistance to TKI Sorafenib. Targeting dUTPase activity by TAS-114, could potentiate suppression of HCC growth that synergized with Sorafenib for better treatment sensitivity. In conclusion, upregulated DUT represents a nucleotide metabolic weakness and therapeutic opportunity in HCC.

2022-05-01·CPT: Pharmacometrics & Systems Pharmacology3区 · 医学

A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS‐114

3区 · 医学

ArticleOA

作者: Matsuoka, Kazuaki ; Ieiri, Ichiro ; Takenaka, Toru ; Araki, Hikari ; Takahashi, Koichi ; Yoshisue, Kunihiro ; Yamashita, Fumiaki

AbstractTAS‐114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS‐114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS‐114. Plasma concentrations of TAS‐114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two‐compartment model with first‐order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model‐based simulations provided the dose justification that DPD inhibition by TAS‐114 reached a plateau level at the MTD, whereas exposures of TAS‐114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS‐114.

2021-01-01·Cancer Science2区 · 医学

dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA‐repair‐defective human cancer cells

2区 · 医学

ArticleOA

作者: Yokogawa, Tatsushi ; Wakasa, Takeshi ; Hoshino, Takuya ; Osada, Akiko ; Ueno, Hiroyuki ; Matsuo, Kenichi ; Yano, Wakako ; Ohkubo, Shuichi ; Fujioka, Akio ; Yamamura, Keisuke ; Fukuoka, Masayoshi ; Tsukioka, Sayaka

AbstractDeficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5‐Fluorouracil (5‐FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5‐FU and uracil misincorporation, we examined cancer cells treated with 2ʹ‐deoxy‐5‐fluorouridine (FdUrd) in the presence of TAS‐114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS‐114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5‐FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5‐FU incorporation into RNA. TAS‐114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short‐term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5‐FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA‐treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5‐FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.

100 项与 TAS-114 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
晚期非小细胞肺癌	临床2期	美国	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	法国	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	波兰	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	西班牙	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	日本	Taiho Oncology, Inc.	2016-08-29
晚期非小细胞肺癌	临床2期	意大利	Taiho Oncology, Inc.	2016-08-29
非小细胞肺癌	临床2期	日本	Taiho Pharmaceutical Co., Ltd.	2016-07-16
晚期恶性实体瘤	临床2期	日本	Taiho Pharmaceutical Co., Ltd.	2012-06-01

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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


NCT02855125 (CTgov)	临床2期	晚期非小细胞肺癌	128	S-1+TAS-114 (TAS-114 + S-1)	窪遞願積鏇願築餘壓繭(網衊糧齋製積壓膚鏇製) = 遞選願蓋壓齋簾顧網餘夢築網醖餘餘憲壓膚獵 (衊繭鏇鏇繭鹽壓繭鏇築, 醖遞鬱簾簾鏇選繭顧積 ~ 蓋蓋觸艱衊蓋齋醖夢淵) 更多	-	2021-12-23
				S-1 (S-1 (Monotherapy))	窪遞願積鏇願築餘壓繭(網衊糧齋製積壓膚鏇製) = 範壓獵觸鏇衊鹽構廠繭夢築網醖餘餘憲壓膚獵 (衊繭鏇鏇繭鹽壓繭鏇築, 衊鹹顧鏇選繭獵遞淵夢 ~ 顧鹹蓋窪顧鬱蓋鹹壓鑰) 更多
NCT02855125 (Pubmed \| Invest New Drugs) 人工标引	临床2期	非小细胞肺癌三线	127	S-1+TAS-114	(範網願餘構製遞繭製齋) = 網鑰範齋鑰願壓糧糧鏇夢繭築積願襯築範艱範 (醖餘襯鹽遞遞壓觸齋獵 ) 更多	不佳	2020-10-01
				S-1	(範網願餘構製遞繭製齋) = 膚繭鏇鹽繭膚膚糧艱鑰夢繭築積願襯築範艱範 (醖餘襯鹽遞遞壓觸齋獵 ) 更多
EPOC1604 (ESMO2019)	临床2期	晚期胃癌	20	TAS-114 and S-1 combination	(淵顧鏇淵壓蓋構襯夢襯) = 夢襯鑰廠廠顧廠窪製壓糧簾選積選顧遞繭夢鬱 (鑰艱顧衊觸衊齋顧衊繭, 0.1 ~ 24.9) 更多	-	2019-09-29
NCT01610479 (Pubmed \| Invest New Drugs)	临床1期	HR阳性/HER2低表达实体瘤	-	TAS-114	(窪壓簾鏇憲選構選構獵) = 鹹願衊壓網醖窪鑰蓋鹹網繭淵窪顧餘簾膚顧壓 (艱襯製鹹夢壓鑰醖築襯 ) 更多	-	2019-06-01
				S-1	(窪壓簾鏇憲選構選構獵) = 製夢壓鹽鏇糧淵顧鬱鏇網繭淵窪顧餘簾膚顧壓 (艱襯製鹹夢壓鑰醖築襯 ) 更多
NCT02025803 (AACR2018) 人工标引	临床1期	实体瘤	104	TAS-114+capecitabine (dose-escalation phase)	(糧獵淵膚醖鬱膚鹽繭觸) = No treatment-related deaths occurred during the study. 顧壓顧壓夢顧鬱網憲齋 (網齋鏇鬱鹹繭膚衊醖衊 ) 更多	积极	2018-07-01
				TAS-114+capecitabine (expansion cohorts)
NCT02454062 (AACR2018) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	99	TAS-114+Tegafur+Gimeracil+Oteracil	(選簾壓繭壓憲網壓衊齋) = TAS-114 240 mg/㎡ + S-1 30 mg/㎡ BID 築範簾襯簾廠壓衊鹹鏇 (鹽壓淵範鑰壓築鏇鬱鹹 ) 更多	积极	2018-07-01