PR-104(PR-104) - 药物靶点：DNA_专利_临床

概要

基本信息

药物类型

小分子化药

别名

PR 104、SN-29244

靶点

DNA

作用方式

抑制剂

作用机制

DNA抑制剂(DNA抑制剂)、DNA烷化剂

治疗领域

肿瘤免疫系统疾病消化系统疾病+ [2]

在研适应症-

非在研适应症

急性淋巴细胞白血病晚期肝细胞癌晚期非小细胞肺癌+ [4]

原研机构

Proacta, Inc.

在研机构-

非在研机构

Proacta, Inc.

权益机构-

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C14H20BrN4O12PS

InChIKeyGZSOKPMDWVRVMG-UHFFFAOYSA-N

CAS号851627-62-8

关联

8

项与 PR-104 相关的临床试验

NCT01037556

/ Unknown status临床1/2期

Phase I/II Study of PR104 in Subjects With Refractory/Relapsed Acute Leukemia Using Adaptive Dose Selection

The current understanding of PR104 justifies the evaluation of PR104 in subjects with relapsed/refractory AML and ALL. These include:
* Hypoxia. Leukemic bone marrow is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Myelotoxicity as the primary toxicity at MTD. In prior clinical studies in subjects with solid tumors PR104 has demonstrated myelotoxicity as the primary toxicity. This observation suggests that PR104 will exert a similar effect on leukemic cells.
* AKR1C3. AML has been reported to exhibit high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic leukemic cells.
* Preclinical data. PR104 has demonstrated impressive activity in an initial study using primary human ALL in a mouse model.
The initial dose finding phase of the study will provide estimates of the activity and toxicity of PR104 in subjects with refractory/relapsed AML, and determine the optimal individualized dose to give each subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). Once a potentially beneficial dose has been determined, an expanded cohort of subjects with AML or ALL will receive PR104 at a uniform dose. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity and acceptable safety in AML to warrant future phase II or phase III studies in this indication.
Primary objectives
* Determine the toxicities and recommended dose of PR104 when administered IV to subjects with relapsed/refractory AML and ALL.
Secondary objectives
* Evaluate the pharmacokinetics (PK) of PR104 and a series of PR104 metabolites
* Evaluate any anti-tumor effects of PR104
* Evaluate the expression of AKR1C3 in bone marrow and leukemic cells
* Evaluate potential biomarkers of hypoxia

开始日期2010-01-01

申办/合作机构

Proacta, Inc.

NCT00862134

/ Terminated临床2期

A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer

The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:
* Aldo-keto reductase 1C3 (AKR1C3). NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.
* Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic positron emission tomography (PET) imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.
* Manageable toxicity. PR104 and docetaxel with Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (MTD) has been identified and the major toxicities of this combination are understood.
The current study will provide an estimate of the activity of PR104 in subjects with NSCLC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.
Primary objectives
• Estimate the response rate (RR) of PR104/docetaxel
Secondary objectives
* Evaluate survival
* Evaluate progression free survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics of PR104 and its metabolites
* Evaluate the pharmacokinetics of docetaxel
* Evaluate the tumor hypoxia using 18F-fluoromisonidazole (18F-MISO) PET imaging
* Collect diagnostic biopsy samples for the determination of AKR1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

开始日期2009-03-01

申办/合作机构

Proacta, Inc.

NCT00862082

/ Terminated临床1/2期

A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
* Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment.
* Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
* Aldo-keto reductase 1C3 (AKR1C3). HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
* Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
Primary objectives
* Phase I: Determine the maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
* Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
Secondary objectives
* Evaluate survival
* Evaluate Progression Free Survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics (PK) of sorafenib, PR104 and PR104 metabolites
* Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

开始日期2009-03-01

申办/合作机构

Proacta, Inc.

100 项与 PR-104 相关的临床结果

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100 项与 PR-104 相关的转化医学

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100 项与 PR-104 相关的专利（医药）

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32

项与 PR-104 相关的文献（医药）

2022-07-01·Cancer gene therapy2区 · 医学

Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411NTR leading to therapeutic benefit

2区 · 医学

Article

作者: Smaill, Jeff B ; Mowday, Alexandra M ; Li, Dan ; Ashoorzadeh, Amir ; Syddall, Sophie P ; Singleton, Dean C ; Guise, Chris P ; Bai, Sally Y ; Wilson, William R ; Patterson, Adam V

Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411^NTR in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411^NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411^NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411^NTR with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.

2022-02-01·Cancer gene therapy2区 · 医学

Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours

2区 · 医学

Article

作者: Kubiak, Aleksandra M ; Smaill, Jeff B ; Theys, Jan ; Ackerley, David F ; Lambin, Philippe ; Guise, Christopher P ; Chan-Hyams, Jasmine V E ; Ashoorzadeh, Amir ; Dubois, Ludwig J ; Mowday, Alexandra M ; Minton, Nigel P ; Patterson, Adam V

Necrosis is a typical histological feature of solid tumours that provides a selective environment for growth of the non-pathogenic anaerobic bacterium Clostridium sporogenes. Modest anti-tumour activity as a single agent encouraged the use of C. sporogenes as a vector to express therapeutic genes selectively in tumour tissue, a concept termed Clostridium Directed Enzyme Prodrug Therapy (CDEPT). Here, we examine the ability of a recently identified Neisseria meningitidis type I nitroreductase (NmeNTR) to metabolise the prodrug PR-104A in an in vivo model of CDEPT. Human HCT116 colon cancer cells stably over-expressing NmeNTR demonstrated significant sensitivity to PR-104A, the imaging agent EF5, and several nitro(hetero)cyclic anti-infective compounds. Chemical induction of necrosis in human H1299 xenografts by the vascular disrupting agent vadimezan promoted colonisation by NmeNTR-expressing C. sporogenes, and efficacy studies demonstrated moderate but significant anti-tumour activity of spores when compared to untreated controls. Inclusion of the pre-prodrug PR-104 into the treatment schedule provided significant additional activity, indicating proof-of-principle. Successful preclinical evaluation of a transferable gene that enables metabolism of both PET imaging agents (for vector visualisation) and prodrugs (for conditional enhancement of efficacy) is an important step towards the prospect of CDEPT entering clinical evaluation.

2018-08-01·Biochemical pharmacology2区 · 医学

Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A

2区 · 医学

Article

作者: Gu, Yongchuan ; Wilson, William R ; Liyanage, H D Sarath ; Stornetta, Alessia ; Sturla, Shana J ; Deng, Kai-Cheng Kieren ; Danielli, Sara

PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R² = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.

100 项与 PR-104 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	PR-104	-	DB05968

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
急性淋巴细胞白血病	临床2期	美国	Proacta, Inc.	2010-01-01
难治性急性白血病	临床2期	美国	Proacta, Inc.	2010-01-01
难治性急性髓细胞白血病	临床2期	美国	Proacta, Inc.	2010-01-01
晚期肝细胞癌	临床2期	美国	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	中国香港	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	新加坡	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	中国台湾	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	美国	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	加拿大	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	新西兰	Proacta, Inc.	2009-03-01

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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


NCT01037556 (ASCO2013)	临床1/2期	复发难治性急性淋巴细胞白血病	50	PR104	壓鏇積遞鑰積積製範鏇(鏇選網憲鏇壓網範窪願) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) 憲範鑰獵蓋壓壓築膚範 (獵衊築簾淵蓋顧壓鑰鬱 ) 更多	-	2013-05-20
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	Docetaxel (Docetaxel)	範齋觸膚衊糧鬱繭範艱 = 齋觸鏇膚築壓顧襯醖選遞衊淵窪顧獵鹹繭鏇顧 (淵鹹繭醖製鹹齋艱範鏇, 廠顧夢遞構鑰鹽願鬱鹽 ~ 選簾蓋壓鬱鏇壓憲築襯) 更多	-	2013-01-10
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	PR104+Docetaxel (PR104 + Docetaxel)	範齋觸膚衊糧鬱繭範艱 = 願壓壓網窪艱襯糧鑰願遞衊淵窪顧獵鹹繭鏇顧 (淵鹹繭醖製鹹齋艱範鏇, 夢蓋憲簾觸衊選餘淵遞 ~ 鹹構襯繭繭範鹽網醖構) 更多	-	2013-01-10
NCT00544674 (CTgov)	临床2期	复发性小细胞肺癌	5	F-18-fluoromisonidazole+PR104	鑰蓋糧鹹築襯構襯憲鹽 = 淵鹹壓願網選顧製衊製鏇餘鹹鬱選製鑰獵夢糧 (鹹窪鹽鏇蓋憲憲網廠齋, 蓋襯製襯餘淵齋醖齋構 ~ 願蓋窪網艱觸簾鹹鏇顧) 更多	-	2011-07-07
ASCO2010	临床1期	实体瘤	26	PR104	鏇艱積窪鏇顧繭構鹹遞(製鹹壓憲鹹積醖鏇積製) = 顧衊築獵襯構觸築廠選鬱夢廠築顧鹽窪蓋顧鑰 (鑰鹽襯窪襯窪壓壓鏇簾, 0.11)	-	2010-05-20
ASCO2008	临床1期	实体瘤	-	PR-104	夢網夢觸鹽選襯願鹽壓(願餘醖憲憲鏇醖顧醖遞) = 糧餘襯簾製網餘壓獵蓋網獵繭襯窪網構選鹽醖 (壓壓鏇膚淵鑰製衊淵網 )	-	2008-05-20
ASCO2008	临床1期	晚期癌症	23	PR-104 + Gemcitabine	觸艱築餘築襯醖遞憲夢(築鹹餘製鹽觸積鬱淵築) = 艱餘衊壓鏇膚選簾範構築蓋襯鹹構繭簾齋範衊 (選鬱繭觸獵鬱餘齋鬱衊 )	-	2008-05-20
ASCO2008	临床1期	实体瘤	13	PR-104	鹽齋夢遞襯壓築觸窪鹹(艱繭膚壓積觸鹽築鏇襯) = 鏇選繭積齋蓋鹽觸淵鏇鏇壓構糧鑰艱蓋糧願襯 (遞襯繭夢淵壓壓鑰淵衊 )	-	2008-05-20