Tasidotin Hydrochloride(Tasidotin Hydrochloride) - 药物靶点：β-tubulin_在研适应症：实体瘤_专利_临床

概要

基本信息

药物类型

合成多肽

别名

SYN-D、Synthadotin、Tasidotin

+ [9]

靶点

β-tubulin

作用机制

β-tubulin抑制剂(Tubulin beta inhibitors)

治疗领域

肿瘤

在研适应症

实体瘤

非在研适应症

去势抵抗性前列腺癌局部晚期非小细胞肺癌局部晚期黑色素瘤

原研机构

Abbott Laboratories

在研机构

The University of Texas Health Science Center At Tyler

ILEX Oncology, Inc.

非在研机构

Genzyme Corp.

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C32H58N6O5.ClH

InChIKeyOOKIODJYZSVHDO-QMYFOHRPSA-N

CAS号623174-20-9

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Sequence Code 122039

关联

5

项与 Tasidotin Hydrochloride 相关的临床试验

EUCTR2011-000124-15-DE

/ Not yet recruiting临床1/2期

An Open-Label, Multi-Center Phase I/IIa Dose Escalation Study to Investigate the Safety and Tolerability of Multiple Doses of Oral Tasidotin HCL in Patients with Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphomas

开始日期2011-06-22

申办/合作机构-

EUCTR2009-011498-34-DE

/ Not yet recruitingN/A

An Open-Label, Multi-Center Phase I/II Dose Escalation Study to Investigate the Safety and Tolerability of Multiple Doses of Oral Tasidotin HCL in Patients with Advanced Solid Tumors (part A), and combination of Oral Tasidotin HCl with Intravenous DTIC in Chemotherapy Naive Patients with Malignant Melanoma (part B).

开始日期2009-10-22

申办/合作机构-

NCT00078455

/ Completed临床2期

A Phase II Study of ILX651 Administered Intravenously Daily for Five Consecutive Days Once Every 3 Weeks in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma

This is a Phase II, non-randomized, open label study of ILX651 in patients with locally advanced or metastatic non-small cell lung carcinoma (NSCLC). Approximately 60 patients will be enrolled in this study that is expected to last 18 months. All patients will be treated with ILX651 administered intravenously (IV) daily for 5 consecutive days once every 21 days. The primary objective of this study is to determine the overall response rate. The secondary objectives are to determine the progression free survival, duration of response, time to tumor progression, survival, safety/tolerability of ILX651, and to evaluate pharmacokinetic profile.

开始日期2003-12-01

申办/合作机构

Genzyme Corp.

100 项与 Tasidotin Hydrochloride 相关的临床结果

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100 项与 Tasidotin Hydrochloride 相关的转化医学

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100 项与 Tasidotin Hydrochloride 相关的专利（医药）

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16

项与 Tasidotin Hydrochloride 相关的文献（医药）

2013-10-01·Molecular and Cellular Biochemistry3区 · 生物学

Mechanism of mitotic arrest induced by dolastatin 15 involves loss of tension across kinetochore pairs

3区 · 生物学

Article

作者: Manu Lopus

Dolastatin 15 (DL15) is a potent, tubulin-targeted, vinca-site binding, anticancer agent that induces mitotic arrest and inhibit cell proliferation in a variety of cell types. Several analogs of DL15, including LU 103793 and tasidotin, have been progressed to clinical trials for different types of cancer. DL15 has been known to interfere with cellular microtubules and purified tubulin in vitro. However, the molecular mechanism with which the peptide arrests cells in mitosis is poorly understood. This study reports a possible antimitotic mechanism of action of DL15. DL15 inhibited HeLa cell proliferation in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 2.8 ± 0.3 nM, induced mitotic arrest, disrupted cellular microtubules near its IC50 for cell proliferation, and inhibited the re-polymerization of cellular microtubules. By staining the centrosomes of DL15-treated cells with anti-γ tubulin antibodies, the study found a significant reduction in interpolar distances in mitotic HeLa cells, indicating a disruption in the normal assembly dynamics of the microtubules. The study further found that DL15 induced a loss of tension across the kinetochore pairs as indicated by a reduction in interkinetochore distance. In response to this loss of tension, the tension-sensing checkpoint protein BuBR1 accumulated at the kinetochores, promoting mitotic arrest. In vitro, DL15 promoted formation of curved and fragmented polymers of microtubule proteins and inhibited tubulin decay in a manner similar to vinca-site binding agents such as phomopsin A. Together, the data indicate that the mitotic arrest induced by DL15 involves a loss of tension across the kinetochore pairs due to disruption of normal assembly dynamics of microtubules.

2009-10-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents

4区 · 医学

Article

作者: Rebecca G. Bagley ; Roy D. Krumbholz ; Steven M. Schmid ; Jennifer L. Crawford ; Stephanie D. Roth ; Leslie S. Kurtzberg ; Min Yao ; Cecile Rouleau ; Beverly A. Teicher

PURPOSEThe dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared.METHODSMouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts.RESULTSThe IC(90) concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC(90)s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect.CONCLUSIONSBringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

2009-07-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates

4区 · 医学

Article

作者: Patrick Thompson ; Lindsay B. Kilburn ; Brian W. Gibson ; Susan M. Blaney ; Stacey L. Berg ; Peter L. Bonate ; Robert Dauser ; Leticia McGuffey ; Jed G. Nuchtern

PURPOSETo evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model.METHODSTasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods.RESULTSThe mean (+/-SD) CSF:plasma AUC ratio for tasidotin was 1.1 +/- 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean +/- SD) were 30 +/- 10, 54 +/- 19 and 12 +/- 2 microM min, and apparent plasma half-lives were 27 +/- 4, 229 +/- 73 and 100 +/- 29 min. The plasma clearance of tasidotin was 44 +/- 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 +/- 10 microM min and 96 +/- 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate.CONCLUSIONSTasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.

100 项与 Tasidotin Hydrochloride 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06009	-	-	-

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
实体瘤	临床前	美国	ILEX Oncology, Inc.	2004-04-01
实体瘤	临床前	美国	The University of Texas Health Science Center At Tyler	2004-04-01
去势抵抗性前列腺癌	药物发现	美国	Genzyme Corp.	2004-05-04
局部晚期非小细胞肺癌	药物发现	美国	Genzyme Corp.	2003-12-01
局部晚期黑色素瘤	药物发现	美国	Genzyme Corp.	2003-08-01

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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


ASCO2005	临床2期	转移性黑色素瘤 \| 局部晚期黑色素瘤	65	ILX651 28mg/m2	(範鹽鏇壓憲觸構鏇鏇鹽) = 觸壓衊鹽艱鏇積範膚齋糧襯選製積衊範襯獵觸 (簾繭選夢餘壓製獵鑰夢 ) 更多	-	2005-06-01
ASCO2004	临床1期	HR阳性/HER2低表达实体瘤	93	SYN-D	(壓積廠網選衊淵築願艱) = 構構鹽淵構鏇齋網壓遞網憲餘襯廠鬱製壓繭觸 (網醖糧膚範齋鹹淵壓蓋 ) 更多	-	2004-07-15