Imidacrine(Imidacrine) - 药物靶点：FLT3 x Top I x Top II_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Imidazoloacridine、Symadex、Symadex Pathfinder

+ [6]

靶点

FLT3 x Top I x Top II

作用方式

抑制剂

作用机制

FLT3抑制剂(酪氨酸蛋白激酶受体FLT3抑制剂)、TOP1抑制剂(DNA拓扑异构酶I抑制剂)、Top II抑制剂(拓扑异构酶II抑制剂)

治疗领域

肿瘤消化系统疾病皮肤和肌肉骨骼疾病+ [4]

在研适应症-

非在研适应症

急性髓性白血病乳腺癌溃疡性结肠炎+ [5]

原研机构

University of Bradford

在研机构-

非在研机构

Antisoma, Inc.

Sarossa Capital Ltd.

BTG International Ltd.

+ [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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关联

2

项与 Imidacrine 相关的临床试验

EUCTR2005-004257-96-GB

/ Not yet recruiting临床2期

Phase II Study with Symadex (C-1311) in Women with Metastatic Breast Cancer after Anthracycline and Taxane Failure

开始日期2006-02-20

申办/合作机构-

EUCTR2005-004258-28-GB

/ Not yet recruiting临床2期

Phase II Study with Symadex (C-1311) in Patients with Metastatic Colorectal Cancer after Oxaliplatin and/or Irinotecan Failure

开始日期2006-01-25

申办/合作机构-

100 项与 Imidacrine 相关的临床结果

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100 项与 Imidacrine 相关的转化医学

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100 项与 Imidacrine 相关的专利（医药）

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50

项与 Imidacrine 相关的文献（医药）

2022-09-01·Biomedicine & Pharmacotherapy

Lysosomal sequestration of weak base drugs, lysosomal biogenesis, and cell cycle alteration

Article

作者: Pastvova, N ; Dostalova, K ; Dolezel, P ; Mlejnek, P ; Havlasek, J

Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.

2022-05-01·Bioorganic Chemistry2区 · 化学

Design, synthesis, and biological evaluation of novel pyrido-dipyrimidines as dual topoisomerase II/FLT3 inhibitors in leukemia cells

2区 · 化学

Article

作者: Nayl, A A ; Abdelhameid, Mohammed K ; Karam Farag, Ahmed ; Omar, Hany A ; Kandeel, Manal M ; Musa, Arafa ; Elmowafy, Mohammed ; Bukhari, Syed N A ; Shaker, Mohamed E ; Mohamed, Fatma E A ; Al-Sanea, Mohammad M ; Abdelgawad, Mohamed A ; Lamie, Phoebe F ; Ali, Sameeha M

Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.

2019-05-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

Electrochemical simulation of metabolism for antitumor-active imidazoacridinone C-1311 and in silico prediction of drug metabolic reactions

3区 · 医学

Article

作者: Żelaszczyk, Dorota ; Potęga, Agnieszka ; Mazerska, Zofia

The metabolism of antitumor-active 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) has been investigated widely over the last decade but some aspects of molecular mechanisms of its metabolic transformation are still not explained. In the current work, we have reported a direct and rapid analytical tool for better prediction of C-1311 metabolism which is based on electrochemistry (EC) coupled on-line with electrospray ionization mass spectrometry (ESI-MS). Simulation of the oxidative phase I metabolism of the compound was achieved in a simple electrochemical thin-layer cell consisting of three electrodes (ROXY^™, Antec Leyden, the Netherlands). We demonstrated that the formation of the products of N-dealkylation reactions can be easily simulated using purely instrumental approach. Newly reported products of oxidative transformations like hydroxylated or oxygenated derivatives become accessible. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass ion data and tandem mass spectrometry experiments. In silico prediction of main sites of C-1311 metabolism was performed using MetaSite software. The compound was evaluated for cytochrome P450 1A2-, 3A4-, and 2D6-mediated reactions. The results obtained by EC were also compared and correlated with those of reported earlier for conventional in vitro enzymatic studies in the presence of liver microsomes and in the model peroxidase system. The in vitro experimental approach and the in silico metabolism findings showed a quite good agreement with the data from EC/ESI-MS analysis. Thus, we conclude here that the electrochemical technique provides the promising platform for the simple evaluation of drug metabolism and the reaction mechanism studies, giving first clues to the metabolic transformation of pharmaceuticals in the human body.

1

项与 Imidacrine 相关的新闻（医药）

2007-12-11

·BioSpace

Xanthus Pharmaceuticals, Inc.'s Symadex Demonstrates Ability to Increase Spinal Cord Remyelination in Multiple Sclerosis Model

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Xanthus Pharmaceuticals, Inc. today presented preclinical data further supporting the potential for Symadex™ to reverse the clinical and pathological signs of multiple sclerosis (MS), including new data demonstrating increased spinal cord remyelination. The study was presented by Dr. Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario and researchers from Xanthus at a meeting of the Multiple Sclerosis Society of Canada in Banff, Canada.

100 项与 Imidacrine 相关的药物交易

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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
急性髓性白血病	临床2期	美国	Sarossa Capital Ltd.	-
乳腺癌	临床2期	-	Antisoma, Inc.	-
乳腺癌	临床2期	欧洲	Sarossa Capital Ltd.	-
乳腺癌	临床2期	-	University of Bradford	-
乳腺癌	临床2期	-	BTG International Ltd.	-
结直肠癌	临床2期	-	Antisoma, Inc.	-
结直肠癌	临床2期	英国	Sarossa Capital Ltd.	-
结直肠癌	临床2期	-	BTG International Ltd.	-
结直肠癌	临床2期	-	University of Bradford	-
多发性硬化症	临床2期	美国	Sarossa Capital Ltd.	-

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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


ASCO2008	临床2期	晚期乳腺癌	53	C1311	蓋築鑰繭獵鹹襯願餘觸(糧築網窪鏇蓋願齋襯繭) = 顧蓋選糧齋製築襯鏇獵廠鬱膚鹹蓋構鏇獵鹽蓋 (餘窪願選窪廠蓋艱齋築 ) 更多	-	2008-05-20
C-1311 (ASCO2008)	临床1期	HR阳性/HER2低表达实体瘤	36	C-1311	(簾齋願壓齋鹹觸鹹膚蓋) = 壓願顧淵夢蓋蓋網範範構選簾遞範齋範蓋顧製 (願淵壓夢觸窪糧醖選繭 ) 更多	-	2008-05-20
ASCO2006	临床1期	HR阳性/HER2低表达实体瘤	16	C-1311	(鹹餘鹽鬱壓觸鑰鑰選艱) = Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. 築艱鬱獵鑰鬱遞壓築廠 (繭願遞膚醖選簾襯繭鬱 ) 更多	-	2006-06-20