ARQ-761(ARQ-761) - 药物靶点：NQO1_在研适应症：胰腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

NQO1

作用机制

NQO1抑制剂(苯醌还原酶-1抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

最高研发阶段临床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

2

项与 ARQ-761 相关的临床试验

NCT02514031 / Terminated临床1期IIT

A Phase I/Ib, Single-Arm, Open-Label, Multi-Center Trial Using ARQ-761 (Beta-Lapachone) Treatment With Gemcitabine/Nab-Paclitaxel Chemotherapy In Metastatic, Unresectable, Or Recurrent Pancreatic Cancer

This is a study of ARQ-761 (beta-lapachone) with gemcitabine/nab-paclitaxel chemotherapy in subjects with advanced (metastatic, unresectable, or recurrent) pancreatic cancer that has not been treated with gemcitabine.

开始日期2016-03-24

申办/合作机构

The University of Texas Southwestern Medical Center

NCT01502800 / Completed临床1期IIT

A Phase 1 Dose Escalation and Pharmacodynamic Study of ARQ 761 (Beta-Lapachone) in Adult Patients With Advanced Solid Tumors

Primary Objective:
To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of ARQ 761 administered intravenously.
Secondary Objectives:
To determine the pharmacokinetic profile of ARQ 761 To assess the preliminary anti-tumor activity of aRQ 761

开始日期2011-12-29

申办/合作机构

The University of Texas Southwestern Medical Center

100 项与 ARQ-761 相关的临床结果

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100 项与 ARQ-761 相关的转化医学

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100 项与 ARQ-761 相关的专利（医药）

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9

项与 ARQ-761 相关的文献（医药）

2019-12-01·Nanoscale Research Letters3区 · 材料科学

Mesoporous Silica Nanoparticle–Based Combination of NQO1 Inhibitor and 5-Fluorouracil for Potent Antitumor Effect Against Head and Neck Squamous Cell Carcinoma (HNSCC)

3区 · 材料科学

ArticleOA

作者: Xu, Zhiwei ; Lei, Dongchun ; Wang, Jianbo ; Sun, Hongbin ; Chen, Jing ; Zhu, Cailiang ; Gao, Shanjun ; Zhang, Shuai ; Du, Pengqiang ; Zhang, Shuzhen

AbstractHead and neck squamous cell carcinomas (HNSCC) are one of the deadliest forms of cancer, and 90% of its origin is from squamous cells. NAD(P)H:quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in squamous cell carcinoma, plays an important role in proliferation and chemoresistance. The main aims were to study the inhibitory effect of ß-lapachone (ARQ761 in clinical form) in HNSCC and to study the combinational effect of 5-FU and ß-lap in improving the therapeutic efficacy in HNSCC. Lipid bilayer–assembled mesoporous silica nanoparticles loaded with 5-FU/ß-lap were prepared and studied for its physicochemical and biological properties. ß-lap showed a concentration-dependent inhibition of NQO1 enzyme activity in Cal33 cells. Notably, significant inhibitory effect was observed at a dose of 20–50 μg/ml of ß-lap. Combination of 5-FU+ß-lap resulted in lower cell viability; most notably, 5-FU/ß-lap-loaded mesoporous silica nanoparticles (FNQ-MSN) exhibited significantly lower cell viability compared with that of any of the individual drug or physical combinations. ß-lap resulted in a decrease in the protein band of NQO1 compared with control; however, most notable decrease in the NQO1 level was observed in the FNQ-MSN-treated cell group. FNQ-MSN resulted in more than 60% of cell apoptosis (early and late apoptosis) and predominant nuclear fragmentation of cancer cells indicating the superior anticancer effect of a carrier-based combination regimen. Notable decrease in tumor volume was observed with the physical mixture of 5-FU+ß-lap; however, combined treatment of carrier-based 5-FU and ß-lap (FNQ-MSN) significantly delayed the tumor growth and prolonged the survival of tumor-bearing xenograft mice. These findings suggest the potential of NQO1 inhibitor in enhancing the chemotherapeutic potential of 5-FU in the treatment of HNSCC.

2019-04-15·Clinical Cancer Research1区 · 医学

NQO1-dependent, Tumor-selective Radiosensitization of Non–small Cell Lung Cancers

1区 · 医学

Article

作者: Boothman, David A. ; Singh, Naveen ; Williams, Noelle S. ; Xie, Xian-Jin ; Beg, Muhammad S. ; Motea, Edward A. ; Kilgore, Jessica A. ; Bey, Erik A. ; Gerber, David E. ; Huang, Xiumei

AbstractPurpose:Development of tumor-specific therapies for the treatment of recalcitrant non–small cell lung cancers (NSCLC) is urgently needed. Here, we investigated the ability of β-lapachone (β-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that overexpress NAD(P)H:Quinone Oxidoreductase 1 (NQO1).Experimental Design:The mechanism of lethality of low-dose IR in combination with sublethal doses of β-lap was evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograft models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus cotreatments were performed to validate therapeutic efficacy and mechanism of action.Results:β-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased double-strand break (DSB) lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 β-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (∼12 units) of any normal tissue. PK/PD responses confirm that IR + β-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels, and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, whereas low NQO1 levels and high levels of catalase in associated normal tissue were protective.Conclusions:Our data suggest that combination of sublethal doses of β-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + β-lap against patients with NQO1+ NSCLCs.

2018-10-01·British Journal of Cancer1区 · 医学

Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis

1区 · 医学

Article

作者: Fatunde, Oluwatomilade ; Xie, Yang ; Schwartz, Brian ; Frankel, Arthur E ; Putnam, William C ; Gerber, David E ; Dowell, Jonathan E ; Arriaga, Yull ; Kallem, Raja Reddy ; Bisen, Ajit ; Boothman, David A ; Meek, Claudia C ; Beg, M Shaalan ; Bolluyt, Joyce ; Fattah, Farjana ; Subramaniyan, Indhumathy ; Leff, Richard D ; Sarode, Venetia ; Luo, Xin ; Dong, Ying

BACKGROUNDNAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death.METHODSWe performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200).RESULTSA total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m² as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06).CONCLUSIONSARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

100 项与 ARQ-761 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
胰腺癌	临床2期	-	ArQule, Inc.	-
实体瘤	药物发现	美国	Merck GmbH	2018-08-12
晚期恶性实体瘤	药物发现	美国	-	2011-12-29

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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


NCT01502800 (Pubmed \| Med J Aust)	临床1期	肿瘤	42	ARQ 761	(網膚齋壓顧壓範遞壓簾) = reflecting possible methemoglobinaemia 構鏇鏇願範構壓廠窪鬱 (製鑰鑰蓋鹹膚顧網製鹹 ) 更多	-	2018-10-01
ASCO2017	临床1期	肿瘤	42	ARQ 761	淵獵鬱觸夢淵齋願鬱淵(壓願願鑰膚鹹鏇蓋顧鑰) = 膚鬱鏇膚獵鏇積衊糧鑰願襯鏇齋繭壓憲夢襯網 (襯簾壓鏇範築齋淵製觸 ) 更多	积极	2017-05-30