巴他布林酸钠(Batabulin Sodium) - 药物靶点：β-tubulin_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Batabulin (USAN/INN)、巴他布林

+ [8]

靶点

β-tubulin

作用机制

β-tubulin抑制剂(Tubulin beta inhibitors)

治疗领域

肿瘤消化系统疾病神经系统疾病+ [2]

在研适应症-

非在研适应症

乳腺癌结直肠癌胶质瘤+ [4]

原研机构

Amgen, Inc.

在研机构-

非在研机构

Tularik, Inc.

Amgen, 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)终止

特殊审评-

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结构

分子式C13H7F6NNaO3S

InChIKeyRRFNAEBCEOAASM-UHFFFAOYSA-N

CAS号195533-98-3

查看全部结构式(2)

序列信息

Sequence Code 9827723

关联

3

项与巴他布林酸钠相关的临床试验

NCT00057382 / Terminated临床2/3期

T138067 Versus Doxorubicin in Chemotherapy-Naive, Unresectable, Hepatocellular Carcinoma Patients

This is an international, multicenter, randomized study of intravenous T138067 versus intravenous doxorubicin in hepatocellular carcinoma (liver cancer). Patients can not have been treated before with chemotherapy and surgery is not recommended for their cancer. A total of 750 subjects will be enrolled in this study.

开始日期2003-03-01

申办/合作机构

Tularik, Inc.

NCT00022243 / Unknown status临床2期

A Phase II, Open Label Study Of T138067-Sodium In A Second-Line Setting In Non-Small-Cell Lung Cancer Patients With Locally Advanced Or Metastatic Disease Who Have Failed First-Line Therapy With a Taxane

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase II trial to study the effectiveness of T138067 in treating patients who have locally advanced or metastatic non-small cell lung cancer that has not responded to previous chemotherapy.

开始日期2000-10-01

申办/合作机构

Tularik, Inc.

NCT00003359 / Completed临床1期IIT

Phase I Dose Escalation Study to Evaluate the Safety of T138067-Sodium in Patients With Advanced Refractory Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I trial to study the effectiveness of T138067 sodium in treating patients with advanced refractory cancer.

开始日期1998-04-01

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

100 项与巴他布林酸钠相关的临床结果

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100 项与巴他布林酸钠相关的转化医学

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100 项与巴他布林酸钠相关的专利（医药）

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8

项与巴他布林酸钠相关的文献（医药）

2019-05-01·Journal of Biological Chemistry2区 · 生物学

Covalent modification of Cys-239 in β-tubulin by small molecules as a strategy to promote tubulin heterodimer degradation

2区 · 生物学

Article

作者: Li, Weimin ; Yan, Wei ; Li, Yong ; Yang, Jianhong ; Qiu, Qiang ; Chen, Lijuan ; Ye, Haoyu

Clinical microtubule-targeting drugs are functionally divided into microtubule-destabilizing and microtubule-stabilizing agents. Drugs from both classes achieve microtubule inhibition by binding different sites on tubulin and inhibiting or promoting polymerization with no concomitant effects on the protein levels of tubulin heterodimers. Here, we have identified a series of small molecules with diverse structures potentially representing a third class of novel tubulin inhibitors that promote degradation by covalent binding to Cys-239 of β-tubulin. The small molecules highlighted in this study include T0070907 (a peroxisome proliferator-activated receptor γ inhibitor), T007-1 (a T0070907 derivative), T138067, N,N'-ethylene-bis(iodoacetamide) (EBI), and allyl isothiocyanate (AITC). Label-free quantitative proteomic analysis revealed that T007-1 promotes tubulin degradation with high selectivity. Mass spectrometry findings showed covalent binding of both T0070907 and T007-01 to Cys-239 of β-tubulin. Furthermore, T007-1 exerted a degradative effect on tubulin isoforms possessing Cys-239 (β2, β4, and β5(β)) but not those containing Ser-239 (β3, β6) or mutant β-tubulin with a C239S substitution. Three small molecules (T138067, EBI, and AITC) also reported to bind covalently to Cys-239 of β-tubulin similarly induced tubulin degradation. Our results strongly suggest that covalent modification of Cys-239 of β-tubulin by small molecules could serve as a novel strategy to promote tubulin heterodimer degradation. We propose that these small molecules represent a third novel class of tubulin inhibitor agents that exert their effects through degradation activity.

2009-07-15·American journal of translational research

Enhancing effectiveness of the MDR-sensitive compound T138067 using advanced treatment with negative modulators of the drug-resistant protein survivin.

Article

作者: Li, Fengzhi ; Cao, Felicia ; Azrak, Rami G ; Ling, Xiang ; Apontes, Pasha ; He, Xiang

Growing evidence indicates that the antiapoptotic protein survivin is a major factor of drug and radiation resistance in cancer cells. However, application of this finding to therapeutic drug combination is largely unexplored. In this study, breast cancer cells were used for treatment with anticancer compounds alone or in combination. We report that T138067, a better drug against multiple drug resistance (MDR) tumor cells than taxol (Shan et al., PNAS 96:5686-91,1999), induces survivin expression and consequently decreases its effectiveness on the induction of cancer cell death. Treatment of breast cancer cells with T138067 induced survivin expression in these cells while showing no effect on Bcl-2, indicating its specificity. Upregulation of survivin by T138067 was concomitant with an increased drug resistance and associated with an increased phosphorylation of Akt and Erk1/2 MAPK, and a decreased phosphorylation of p38 MAPK without affecting the phosphorylation of ErbB2. Therefore, it is possible that inhibition of T138067-induced survivin expression by alternative approaches may sensitize cells to T138067-induced cell death. We found that treatment of breast cancer cells with SN38, the active metabolite of irinotecan, inhibits survivin expression. Intriguingly, inhibition of survivin expression by SN38 was more effective at a low concentration than at the high concentration, which makes SN38 a good survivin modulator. Furthermore, in contrast with the decreased phosphorylation of p38 MAPK after T138067 treatment, inhibition of survivin expression by SN38 was associated with an increased phosphorylation of the p38 MAPK, suggesting opposing signals converging to survivin. Consistent with these observations, T138067 in combination with SN38 strongly induced cell death in comparison with each drug alone. Similarly, sequential combination of resveratrol, a component of red grapes that inhibits survivin expression, with T138067 also provoked massive breast cancer cell death compared with T138067 alone. Together, these results highlight a new concept that unique signaling cross talk converged to survivin may be considered for rational drug combination in the clinic.

2005-01-01·Journal of Medicinal Chemistry1区 · 医学

Sulfonamide Drugs Binding to the Colchicine Site of Tubulin: Thermodynamic Analysis of the Drug−Tubulin Interactions by Isothermal Titration Calorimetry

1区 · 医学

Article

作者: Poddar, Asim ; Surolia, Avadhesha ; Banerjee, Mithu ; Owa, Takashi ; Mitra, Gopa ; Bhattacharyya, Bhabatarak

The discovery of several sulfonamide drugs paved the way toward the synthesis of 6 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide, E7010) and 7 (N-(3-fluoro-4-methoxyphenyl)pentafluorobenzenesulfonamide, T138067), both of which inhibit tubulin polymerization and are under clinical development. A series of diarylsulfonamides containing an indole scaffold was also found to have antimitotic properties, but their mode of interactions with tubulin has remained unidentified so far. In this study, we demonstrate that these sulfonamide drugs bind to the colchicine site of tubulin in a reversible manner. They quenched intrinsic tryptophan fluorescence of tubulin presumably due to drug-induced conformational changes in the protein, but were unable to modulate GTPase activity of tubulin in contrast to colchicine that enhances the same enzymatic activity. Further investigation using isothermal titration calorimetry (ITC) revealed that 5 (N-(5-chloro-7-indolyl)-4-methoxybenzenesulfonamide) afforded a large positive value of heat capacity change (DeltaC(p)() = +264 cal mol(-1) K(-1)) on binding to tubulin, suggesting a substantial conformational transition in the protein along with partial enthalpy-entropy compensation. On the other hand, the 2-chloro regioisomer 2 gave a large negative value of DeltaC(p)() (-589 cal mol(-1) K(-1)) along with complete enthalpy-entropy compensation. This thermodynamic profile was thought to be attributable to a prominent contribution of van der Waals interaction and hydrogen bonding between specific groups in the drug-tubulin complex. These results indicate that a mere alteration in the position of a single substituent chlorine on the indole scaffold has a great influence on the drug-tubulin binding thermodynamics.

100 项与巴他布林酸钠相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06560	-	-	DB16103

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
不可切除的肝细胞癌	临床3期	波多黎各	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	中国	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	美国	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	乌克兰	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	南非	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	新加坡	Tularik, Inc.	2003-03-01
不可切除的肝细胞癌	临床3期	泰国	Tularik, Inc.	2003-03-01
肝癌	临床3期	美国	-	-
肝癌	临床3期	欧洲	-	-
肝癌	临床3期	亚洲	-	-

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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2/3期	肝细胞癌	339	T138067 250 mg/m2	(顧鬱願衊夢鏇鏇鏇簾鏇) = 窪繭範範顧膚餘顧廠鹽餘範糧壓選壓艱製獵網 (齋顧範窪網齋齋獵鹹願 )	不佳	2005-06-01
				DOX 60 mg/m2	(顧鬱願衊夢鏇鏇鏇簾鏇) = 顧範餘蓋選餘顧窪蓋鏇餘範糧壓選壓艱製獵網 (齋顧範窪網齋齋獵鹹願 )