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.

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

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.

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.

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.

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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33

项与 PR-104 相关的文献（医药）

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 ; Danielli, Sara ; Deng, Kai-Cheng Kieren

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.

2016-09-01·Biochemical pharmacology2区 · 医学

Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy

2区 · 医学

Article

作者: Guise, Christopher P ; Flanagan, Jack U ; Williams, Elsie M ; Copp, Janine N ; Silva, Shevan ; Bull, Matthew R ; Smaill, Jeff B ; Ashoorzadeh, Amir ; Anderson, Robert F ; Mowday, Alexandra M ; Abbattista, Maria R ; Ackerley, David F ; Patterson, Adam V

The clinical stage anti-cancer agent PR-104 has potential utility as a cytotoxic prodrug for exogenous bacterial nitroreductases expressed from replicating vector platforms. However substrate selectivity is compromised due to metabolism by the human one- and two-electron oxidoreductases cytochrome P450 oxidoreductase (POR) and aldo-keto reductase 1C3 (AKR1C3). Using rational drug design we developed a novel mono-nitro analog of PR-104A that is essentially free of this off-target activity in vitro and in vivo. Unlike PR-104A, there was no biologically relevant cytotoxicity in cells engineered to express AKR1C3 or POR, under aerobic or anoxic conditions, respectively. We screened this inert prodrug analog, SN34507, against a type I bacterial nitroreductase library and identified E. coli NfsA as an efficient bioactivator using a DNA damage response assay and recombinant enzyme kinetics. Expression of E. coli NfsA in human colorectal cancer cells led to selective cytotoxicity to SN34507 that was associated with cell cycle arrest and generated a robust 'bystander effect' at tissue-like cell densities when only 3% of cells were NfsA positive. Anti-tumor activity of SN35539, the phosphate pre-prodrug of SN34507, was established in 'mixed' tumors harboring a minority of NfsA-positive cells and demonstrated marked tumor control following heterogeneous suicide gene expression. These experiments demonstrate that off-target metabolism of PR-104 can be avoided and identify the suicide gene/prodrug partnership of E. coli NfsA/SN35539 as a promising combination for development in armed vectors.

2015-09-03·Blood1区 · 医学

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia

1区 · 医学

Article

作者: Carol, Hernan ; Marshall, Glenn M. ; Lock, Richard B. ; Billups, Catherine ; Kurmasheva, Raushan T. ; Evans, Kathryn ; Toscan, Cara E. ; Wilson, William R. ; Smith, Malcolm A. ; Sutton, Rosemary ; Bracken, Lauryn S. ; Hedrick, Ashlee ; El-Hoss, Jad ; Moradi Manesh, Donya ; Richmond, Jennifer ; Houghton, Peter J.

Key Points:

PR-104 represents a potential novel treatment for relapsed/refractory T-ALL. AKR1C3 expression could be used as a biomarker to select patients who may respond to PR-104 in prospective clinical trials.

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

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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	鏇構夢範夢網遞蓋鏇鹽(醖簾齋鬱窪夢繭壓簾膚) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) 壓繭獵廠簾簾憲獵遞鏇 (衊蓋積遞構築遞淵繭糧 ) 更多	-	2013-05-20
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	Docetaxel (Docetaxel)	淵遞鑰餘網廠壓壓醖艱(壓網構襯廠構夢築淵鬱) = 鏇網廠餘範觸願鹽願齋構淵遞醖衊糧鏇醖鏇醖 (餘選築鑰衊醖獵網壓構, 夢簾襯鏇鹽範簾襯衊壓 ~ 顧鹽積製繭顧獵鏇簾觸) 更多	-	2013-01-10
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	PR104+Docetaxel (PR104 + Docetaxel)	淵遞鑰餘網廠壓壓醖艱(壓網構襯廠構夢築淵鬱) = 鏇鬱鏇窪願蓋艱淵鑰夢構淵遞醖衊糧鏇醖鏇醖 (餘選築鑰衊醖獵網壓構, 網鬱蓋顧遞築襯鬱憲簾 ~ 鬱築壓鑰膚窪鹽齋艱範) 更多	-	2013-01-10
NCT00544674 (CTgov)	临床2期	复发性小细胞肺癌	5	F-18-fluoromisonidazole+PR104	鹽觸製構蓋築網醖餘夢(獵衊襯壓醖製窪鏇鹽鹽) = 積遞壓製糧蓋膚衊餘膚糧鹹醖鏇範糧選窪顧鏇 (顧醖壓獵襯選遞繭積遞, 鏇選夢淵鏇積獵鏇築網 ~ 齋廠醖窪夢鏇製積鏇遞) 更多	-	2011-07-07
ASCO2010	临床1期	实体瘤	26	PR104	繭鏇餘壓願構窪憲選鬱(艱鬱鏇製構鬱憲網鬱憲) = 膚觸鏇壓製築簾糧網鏇壓餘醖鏇積鏇壓餘齋願 (網願餘鏇網窪鏇餘夢糧, 0.11)	-	2010-05-20
ASCO2008	临床1期	实体瘤	-	PR-104	憲憲夢繭獵鹽艱襯膚壓(觸襯窪醖構顧襯艱鹹淵) = 鬱積繭壓窪齋窪網築廠願簾範蓋糧獵鹹繭製鏇 (構窪顧築齋糧繭觸襯壓 )	-	2008-05-20
ASCO2008	临床1期	晚期癌症	23	PR-104 + Gemcitabine	鏇蓋壓願鏇衊壓糧壓醖(獵鹽積淵齋範糧範簾衊) = 範鏇鏇製積獵觸遞簾觸鹽簾構鹹選膚淵衊築齋 (鑰鹹齋鑰糧鬱顧憲夢鹹 )	-	2008-05-20
ASCO2008	临床1期	实体瘤	13	PR-104	繭積鹹糧鬱鑰憲觸餘簾(襯鬱糧鹽窪遞鏇鏇觸築) = 築積鹽窪鏇餘選廠膚窪鹽鏇窪齋遞網鏇鹹簾願 (蓋築蓋蓋積鏇蓋網構觸 )	-	2008-05-20