OSI-7904L(OSI-7904L) - 药物靶点：TYMS_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [7]

靶点

TYMS

作用机制

TYMS抑制剂(胸苷酸合成酶抑制剂)

治疗领域

肿瘤消化系统疾病感染

在研适应症-

非在研适应症

胆道腺癌晚期恶性实体瘤胆道肿瘤+ [8]

原研机构

Gilead Sciences, Inc.

在研机构-

非在研机构

OSI Pharmaceuticals, Inc.OncoVista Innovative Therapies, Inc.OncoVista, Inc.

+ [1]

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-

结构

分子式C27H24N4O6

InChIKeyBRVFNEZMTRVUGW-QFIPXVFZSA-N

CAS号139987-54-5

关联

5

项与 OSI-7904L 相关的临床试验

EUCTR2004-001155-11-BE / Not yet recruitingN/A

A Randomized, Open Label, Phase II Study of OSI-7904L versus 5-FU/LV as First-Line Treatment in Patients with Unresectable, Locally Advanced or MetastaticAdenocarcinoma of the Biliary Tract - Not available

开始日期2005-02-25

申办/合作机构

OSI Pharmaceuticals, Inc.

NCT00088270 / Completed临床2期

A Randomized, Open Label, Phase II Study of OSI-7904L Versus 5-FU/LV as First-Line Treatment in Patients With Unresectable, Locally Advanced or Metastatic Adenocarcinoma of the Biliary Tract

Multi-center, randomized Phase II study to evaluate the efficacy and safety of OSI-7904Lversus 5 FU/LV in biliary tract cancer.

开始日期2004-08-01

申办/合作机构

OSI Pharmaceuticals, Inc.

NCT00081237 / Completed临床1期

A Phase I Study of OSI-7904L In Combination With Oxaliplatin In Patients With Advanced Colo-Rectal Cancer

RATIONALE: OSI-7904L may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining OSI-7904L with oxaliplatin may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of OSI-7904L and oxaliplatin in treating patients with refractory or recurrent advanced colorectal cancer.

开始日期2004-02-01

申办/合作机构

Eortc

100 项与 OSI-7904L 相关的临床结果

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100 项与 OSI-7904L 相关的转化医学

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100 项与 OSI-7904L 相关的专利（医药）

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62

项与 OSI-7904L 相关的文献（医药）

2009-11-01·Molecular and Biochemical Parasitology4区 · 医学

Catalytic and ligand-binding characteristics of Plasmodium falciparum serine hydroxymethyltransferase

4区 · 医学

Article

作者: Pradipsinh K. Rathod ; Cullen Kt T. Pang ; Julie Bowman ; Joshua H. Hunter ; Ramulu Podutoori ; Ramesh Gujjar ; Devaraja G. Mudeppa

The plant-like, bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) from malaria parasites has been a good target for drug development. Dihydrofolate reductase (DHFR) is inhibited by clinically established antimalarials, pyrimethamine and cycloguanil. Thymidylate synthase (TS) is the target of potent experimental antimalarials such as 5-fluoroorotate and 1843U89. Another enzyme in folate recycling, serine hydroxymethyltransferase (SHMT), produces 5,10-methylenetetrahydrofolate which, in many cells, is required for the de novo, biosynthesis of thymidine and methionine. Thus, the biochemical characterization of malarial SHMT was of interest. The principle, active Plasmodium falciparum SHMT (PfSHMT) was expressed in E. coli and purified using an N-terminal histidine tag. Unlike the plant enzyme, but like the host enzyme, PfSHMT requires the cofactor pyridoxal 5'-phosphate for enzymatic activity. The substrate specificities for serine, tetrahydrofolate, and pyridoxal 5'-phosphate were comparable to those for SHMT from other organisms. Antifolates developed for DHFR and TS inhibited SHMT in the mid-micromolar range, offering insights into the binding preferences of SHMT but clearly leaving room for improved new inhibitors. As previously seen with P. falciparum DHFR-TS, PfSHMT bound its cognate mRNA but not control RNA for actin. RNA binding was not reversed with enzyme substrates. Unlike DHFR-TS, the SHMT RNA-protein interaction was not tight enough to inhibit translation. Another gene PF14_0534, previously proposed to code for an alternate mitochondrial SHMT, was also expressed in E. coli but found to be inactive. This protein, nor DHFR-TS, enhanced the catalytic activity of PfSHMT. The present results set the stage for developing specific, potent inhibitors of SHMT from P. falciparum.

2008-12-01·Clinical Cancer Research1区 · 医学

Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors

1区 · 医学

Article

作者: Syed, Samira ; Horan, Julie ; Berlin, Jordan D. ; Ricart, Alejandro D. ; Drolet, Daniel W. ; Tolcher, Anthony W. ; Chick, Jon ; Papadopoulos, Kyriakos P. ; Vermeulen, Wendy ; Rothenberg, Mace L. ; Rowinsky, Eric K. ; Quaratino-Baker, Charlotte

AbstractPurpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors.Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated.Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity.Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

2008-04-01·Cancer Chemotherapy and Pharmacology4区 · 医学

A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer

4区 · 医学

Article

作者: Sandrine Marreaud ; Juan W Valle ; J Chick ; C Twelves ; A-S Govaerts ; Andrew R Clamp ; Gordon C Jayson ; R Wilson ; Patrick Schöffski ; M Debois ; D Lacombe

PURPOSEOSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.METHODA 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.RESULTSFourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.CONCLUSIONSThe recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

100 项与 OSI-7904L 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	OSI-7904L	-	DB05457

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
胆道肿瘤	临床3期	-	OncoVista Innovative Therapies, Inc.	-
胆道肿瘤	临床3期	-	Gilead Sciences, Inc.	-
结直肠癌	临床3期	-	OncoVista Innovative Therapies, Inc.	-
胃食管交界处癌	临床2期	比利时	OSI Pharmaceuticals, Inc.	2003-10-01
胃食管交界处癌	临床2期	英国	OSI Pharmaceuticals, Inc.	2003-10-01
胃食管交界处癌	临床2期	美国	OSI Pharmaceuticals, Inc.	2003-10-01
胆道肿瘤	临床2期	美国	-	-
胆道肿瘤	临床2期	欧洲	-	-
结直肠癌	临床2期	-	Gilead Sciences, Inc.	-
肿瘤	临床2期	美国	OncoVista, Inc.	-

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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


ASCO2009	临床2期	复发性头颈部鳞状细胞癌	41	OSI-7904L	(餘繭鏇願遞壓糧餘醖鹹) = 觸鹽遞觸遞齋築壓憲簾製醖壓齋鑰鹹觸鏇蓋鬱 (糧憲餘鬱觸獵廠醖蓋齋 )	不佳	2009-05-20
ASCO2005	临床2期	肿瘤	53	OSI-7904L	(蓋獵鑰積艱醖壓鏇壓積) = 淵鑰獵襯鹽製簾窪膚繭築範繭鹽醖蓋廠築膚獵 (願壓鹹鑰衊艱淵淵蓋鏇, 6.2 ~ 28.3) 更多	-	2005-06-01