Talotrexin(Talotrexin) - 药物靶点：DHFR_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Talotrexin Ammonium、Talvesta

+ [3]

靶点

DHFR

作用机制

DHFR抑制剂(二氢叶酸还原酶抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [3]

在研适应症-

非在研适应症

急性淋巴细胞白血病乳腺癌结直肠癌+ [7]

原研机构

Ash Stevens LLC

在研机构-

非在研机构

Spectrum Pharmaceuticals, Inc.

Talon Therapeutics, Inc.

Dana-Farber Cancer Institute, 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-

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结构

分子式C27H27N9O6

InChIKeyNYQPLPNEESYGNO-IBGZPJMESA-N

CAS号113857-87-7

关联

5

项与 Talotrexin 相关的临床试验

NCT00112060 / Withdrawn临床1/2期

A Phase I/II, Open-Label, Multicenter Study of Single Agent PT-523 in the Treatment of Relapsed or Refractory Non-Small Cell Lung Cancer (NSCLC)

This phase I/II, multi-centered, non-randomized trial is designed to determine a safe dose of PT-523 for subjects, and to make preliminary evaluations on the activity of PT-523 as therapy in subjects with NSCLC.

开始日期2008-04-01

申办/合作机构

Spectrum Pharmaceuticals, Inc.

NCT00458744 / Withdrawn临床1期IIT

A Phase I Study Of Talotrexin (PT-523) In Children And Adolescents With Recurrent Solid Tumors Or Recurrent/Refractory Leukemias

RATIONALE: Drugs used in chemotherapy, such as talotrexin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.
PURPOSE: This phase I trial is studying the side effects and best dose of talotrexin in treating young patients with recurrent solid tumors or leukemia that is recurrent or does not respond to treatment.

开始日期2007-02-01

申办/合作机构

The Children's Oncology Group Foundation, Inc.

[+1]

NCT00129558 / Withdrawn临床1/2期

A Phase I/II Study of PT-523 in Patients With Refractory Leukemia

This Phase I/II, multi-centered, non-randomized, trial is designed to determine a safe dose of PT-523 for subjects, and to make preliminary evaluations on the activity of PT-523 as therapy in subjects with refractory leukemia.

开始日期2005-07-01

申办/合作机构

Spectrum Pharmaceuticals, Inc.

100 项与 Talotrexin 相关的临床结果

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100 项与 Talotrexin 相关的转化医学

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100 项与 Talotrexin 相关的专利（医药）

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30

项与 Talotrexin 相关的文献（医药）

2017-11-06·Molecular Pharmaceutics2区 · 医学

Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier

2区 · 医学

Article

作者: Finnell, Richard H. ; Goldman, I. David ; Hoque, Md. Tozammel ; Bendayan, Reina ; Alam, Camille

Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα), known to be regulated by ligand-activated nuclear receptors, such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRα and PCFT, is critical to cerebral folate delivery. Inactivating FRα or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration. The objective of this study was to investigate the role of RFC in folate uptake at the level of the blood-brain barrier (BBB) and its potential regulation by VDR. We detected robust expression of RFC in different in vitro BBB model systems, particularly in immortalized cultures of human cerebral microvascular endothelial cells (hCMEC/D3) and isolated mouse brain capillaries. [³H]-methotrexate uptake by hCMEC/D3 cells at pH 7.4 was inhibited by PT523 and pemetrexed, antifolates with high affinity for RFC. We also showed that activation of VDR through calcitriol (1,25-dihydroxyvitamin D₃) exposure up-regulates RFC mRNA and protein expression as well as function in hCMEC/D3 cells and isolated mouse brain capillaries. We further demonstrated that RFC expression could be down-regulated by VDR-targeting siRNA, further confirming the role of VDR in the direct regulation of this folate transporter. Together, these data suggest that augmenting RFC functional expression could constitute a novel strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by loss of FRα or PCFT function.

2014-01-01·Scandinavian Journal of Rheumatology3区 · 医学

Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients

3区 · 医学

Article

作者: A.H. Gerards ; B.A.C. Dijkmans ; Y.G. Assaraf ; W.F. Lems ; R. Oerlemans ; R.J. Scheper ; J.W. van der Heijden ; G. Jansen

OBJECTIVESAlthough methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production.METHODT cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-α production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry.RESULTSThe new-generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-α production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells.CONCLUSIONIn an ex-vivo setting, novel antifolates elicited marked inhibition of TNF-α production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX.

2010-05-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Clinical potency of methotrexate, aminopterin, talotrexin and pemetrexed in childhood leukemias

4区 · 医学

Article

作者: Robin E. Norris ; Peter C. Adamson

PURPOSERenewed interest in antifols for the treatment of childhood cancers has resulted from identification of novel antifols with broad spectrums of anti-cancer activity and from re-evaluation of the original clinical antifol, aminopterin. In this pre-clinical study we evaluated the in vitro activity of both traditional antifols (methotrexate, aminopterin) and novel antifols (pemetrexed, talotrexin) in childhood acute leukemias and lymphomas.METHODSWe compared the in vitro cytotoxicity of methotrexate, aminopterin, pemetrexed, and talotrexin in a panel of six pediatric leukemia and lymphoma cell lines using the sulforhodamine B assay. In addition to defining a 50% growth inhibitory concentration (IC50) for a 120-h drug exposure, we contrasted the activity of the drugs in the context of clinically achievable (tolerable) drug exposures using the area under the plasma concentration-time curve (AUC). We defined each agent's clinical potency index (CPI) as the AUC achieved with standard pediatric dosing regimens divided by the in vitro IC50.RESULTSAcross all cell lines, talotrexin (median IC50 7 nM) and aminopterin (median IC50 17 nM) had lower IC50's than methotrexate (median IC50 78 nM) and pemetrexed (median IC50 155 nM). However, the CPI for methotrexate (median 0.9) was significantly greater than that for aminopterin (median 0.4). In contrast, pemetrexed had a significantly better CPI (median 13) than the traditional antifols.CONCLUSIONSAminopterin does not appear to offer any advantage over methotrexate for the treatment of childhood ALL. Further study of pemetrexed in childhood leukemias is warranted.

1

项与 Talotrexin 相关的新闻（医药）

2006-11-09

·BioSpace

Hana Biosciences, Inc. To Present Talvesta™ (Talotrexin) For Injection Completed Phase I Clinical Trial In Non Small Cell Lung Cancer At The EORTC-NCI-AACR Symposium

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Hana Biosciences (NASDAQ:HNAB), a biopharmaceutical company focused on advancing cancer care, will present additional data from the completed Phase I trial results for Talvesta™ (talotrexin) for Injection in non small cell lung cancer (NSCLC) at the 18th Annual EORTC-NCI-AACR symposium on “Molecular Targets and Cancer Therapeutics,” in Prague, Czech Republic. Abstract #464: “Pharmacokinetics of talotrexin (PT-523), a novel aminopterin analogue, in patients with non-small cell lung cancer” will be presented on Friday, November 10th from 12:00pm – 2:00pm.

合作AACR会议

100 项与 Talotrexin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06178

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
复发性非小细胞肺癌	临床3期	俄罗斯	Spectrum Pharmaceuticals, Inc.	2008-04-01
非小细胞肺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2008-04-01
非小细胞肺癌	临床2期	俄罗斯	Spectrum Pharmaceuticals, Inc.	2008-04-01
复发性非小细胞肺癌	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2008-04-01
白血病	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2005-07-01
难治性白血病	临床2期	美国	Spectrum Pharmaceuticals, Inc.	2005-07-01
复发性实体肿瘤	临床2期	美国	Dana-Farber Cancer Institute, Inc.	2003-12-01
急性淋巴细胞白血病	临床2期	-	Dana-Farber Cancer Institute, Inc.	-
急性淋巴细胞白血病	临床2期	美国	Talon Therapeutics, Inc.	-
急性淋巴细胞白血病	临床前	-	Astex Pharmaceuticals, Inc.	-

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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


ASCO2006	临床1期	复发性非小细胞肺癌	-	Talotrexin	(築網網廠遞窪願觸鑰築) = 鬱築餘鬱廠憲壓廠窪膚簾構鹽獵鑰鹹願製鹹醖 (襯憲鑰鬱廠餘築網憲願 )	-	2006-06-20