Porfiromycin(Porfiromycin) - 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

Porfiromycin (USAN/INN)、Porfiromycine、Porphyromycin

+ [6]

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

在研适应症-

非在研适应症

头颈部肿瘤原发部位不明恶性肿瘤

原研机构

Yale University

在研机构-

非在研机构

Boehringer Ingelheim GmbH

Yale University

Vion Pharmaceuticals, Inc.

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)-

特殊审评孤儿药 (美国)

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结构

分子式C16H20N4O5

InChIKeyHRHKSTOGXBBQCB-VFWICMBZSA-N

CAS号801-52-5

关联

4

项与 Porfiromycin 相关的临床试验

NCT02183246 / Terminated临床3期

A Phase III, Double-Blind, Randomized, Placebo-Controlled Study of Porfiromycin Used as an Adjuvant to Radiation Therapy in Postoperative Head and Neck Cancer Patients

Determination of efficacy and safety of porfiromycin versus placebo as an adjuvant to radiotherapy in postoperative head and neck a cancer patients as well as assessment of population pharmacokinetic parameters.

开始日期2000-05-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT02209701 / Terminated临床1期

A Phase I Intensive Pharmacokinetic Study of Porfiromycin in Head and Neck Cancer and Other Cancer Patients With Solid Tumors Who Receive Radiation Therapy

Study to determine the steady-state pharmacokinetics and urinary excretion of porfiromycin and major metabolites in head and neck cancer and other cancer patients with solid tumors who receive radiation therapy.

开始日期1999-12-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT00003328 / Completed临床3期

A Phase III Double-Blind, Randomised, Placebo-Controlled Study of Porfiromycin When Used as an Adjuvant to Radiation Therapy in Patients With Head and Neck Cancer

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether radiation therapy followed by porfiromycin is more effective than radiation therapy alone in treating patients with head and neck cancer.
PURPOSE: Randomized double-blinded phase III trial to determine the effectiveness of radiation therapy followed by porfiromycin in treating patients with stage III or stage IV head and neck cancer.

开始日期1997-12-01

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 Porfiromycin 相关的临床结果

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100 项与 Porfiromycin 相关的转化医学

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100 项与 Porfiromycin 相关的专利（医药）

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115

项与 Porfiromycin 相关的文献（医药）

2023-12-12·Microbiology Spectrum

Screening the NCI diversity set V for anti-MRSA activity: cefoxitin synergy and LC-MS/MS confirmation of folate/thymidine biosynthesis inhibition

Article

作者: Gutheil, William G ; Gargvanshi, Shivani ; Heravi, Gioia ; Ayon, Navid J

ABSTRACT New antibacterial agents and agent combinations are urgently needed to combat antimicrobial resistance. A multidimensional chemical library screening strategy was used to identify compounds in the National Cancer Institute (NCI) diversity set V library (1,593 compounds) with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. In this effort, library compounds were screened for anti-MRSA activity in both their original [un-metabolized (UM)] and human liver microsome-metabolized [post-metabolized (PM)] forms and in the absence and presence of sub-minimum inhibitory concentration (MIC) levels of cefoxitin. This strategy allows for the identification of intrinsically active agents, agents with active metabolites, and agents that can act synergistically with cefoxitin. Sixteen UM compounds with MICs ≤ 12.5 µM were identified. No agents with substantially enhanced activity after microsomal metabolism were found. Several agents showed significant apparent synergy with cefoxitin, and checkerboard assays were used to confirm synergy for four of these (celastrol, porfiromycin, 4-quinazolinediamine, and teniposide). A follow-up comparative screen in the absence and presence of 4-µM thymidine was used to identify three agents as likely folate/thymidine biosynthesis inhibitors. A liquid chromatography–mass spectrometry (LC-MS/MS) assay for deoxythymidine triphosphate (dTTP) was used to confirm these three as suppressing dTTP biosynthesis in MRSA. Bactericidal vs bacteriostatic activity was also evaluated. This study further demonstrates the utility of comparative library screening to identify novel bioactive agents with interesting synergies and biological activities. The identification of several folate/thymidine biosynthesis inhibitors from this small screen indicates that this pathway is a viable target for new drug discovery efforts. IMPORTANCE New antibacterial agents are urgently needed to counter increasingly resistant bacteria. One approach to this problem is library screening for new antibacterial agents. Library screening efforts can be improved by increasing the information content of the screening effort. In this study, we screened the National Cancer Institute diversity set V against methicillin-resistant Staphylococcus aureus (MRSA) with several enhancements. One of these is to screen the library before and after microsomal metabolism as means to identify potential active metabolites. A second enhancement is to screen the library in the absence and presence of sub-minimum inhibitory concentration levels of another antibiotic, such as cefoxitin in this study. This identified four agents with synergistic activity with cefoxitin out of 16 agents with good MRSA activity alone. Finally, active agents from this effort were counter-screened in the presence of thymidine, which quickly identified three folate/thymidine biosynthesis inhibitors, and also screened for bactericidal vs bacteriostatic activity.

2007-08-01·Clinical Oncology2区 · 医学

Bioreductive Drugs: from Concept to Clinic

2区 · 医学

Review

作者: KJ Williams ; Stephanie McKeown ; RL Cowen

One of the key issues for radiobiologists is the importance of hypoxia to the radiotherapy response. This review addresses the reasons for this and primarily focuses on one aspect, the development of bioreductive drugs that are specifically designed to target hypoxic tumour cells. Four classes of compound have been developed since this concept was first proposed: quinones, nitroaromatics, aliphatic and heteroaromatic N-oxides. All share two characteristics: (1) they require hypoxia for activation and (2) this activation is dependent on the presence of specific reductases. The most effective compounds have shown the ability to enhance the anti-tumour efficacy of agents that kill better-oxygenated cells, i.e. radiation and standard cytotoxic chemotherapy agents such as cisplatin and cyclophosphamide. Tirapazamine (TPZ) is the most widely studied of the lead compounds. After successful pre-clinical in vivo combination studies it entered clinical trial; over 20 trials have now been reported. Although TPZ has enhanced some standard regimens, the results are variable and in some combinations toxicity was enhanced. Banoxantrone (AQ4N) is another agent that is showing promise in early phase I/II clinical trials; the drug is well tolerated, is known to locate in the tumour and can be given in high doses without major toxicities. Mitomycin C (MMC), which shows some bioreductive activation in vitro, has been tested in combination trials. However, it is difficult to assign the enhancement of its effects to targeting of the hypoxic cells because of the significant level of its hypoxia-independent toxicity. More specific analogues of MMC, e.g. porfiromycin and apaziquone (EO9), have had variable success in the clinic. Other new drugs that have good pre-clinical profiles are PR 104 and NLCQ-1; data on their clinical safety/efficacy are not yet available. This paper reviews the pre-clinical data and discusses the clinical studies that have been reported.

2007-01-01·Chemical and Pharmaceutical Bulletin4区 · 医学

Solvolysis Study of Cycliciminomitomycins

4区 · 医学

Article

作者: Na, Younghwa

The solvolysis rates for the substituted C(7)-cyclohexylamino- or C(8)-cyclohexyliminomitomycins 8-19 were determined in buffered methanolic solutions (0.06 M bis-Tris.HCl, pH: 5.5) at 25 degrees C and then compared with mitomycin C (1) and porfiromycin. Kinetic studies showed that C(8)-cyclohexyliminomitomycins 8-13 underwent solvolysis 150-230 times faster than mitomycin C (1) to give C(1)-methoxymitosene products. The solvolysis rates were slightly faster than that reported for 6. The C(7)-(2'-hydroxy)cyclohexylaminomitomycins 16-19 exhibited comparable solvolysis rates with 1 and porfiromycin.

100 项与 Porfiromycin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D05572	-	-	DB06478

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
原发部位不明恶性肿瘤	临床3期	美国	Yale University	1992-11-01
头颈部肿瘤	临床3期	美国	Vion Pharmaceuticals, Inc.	-
头颈部肿瘤	临床3期	美国	Vion Pharmaceuticals, Inc.	-