Delving into the Latest Updates on Batabulin Sodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Batabulin (USAN/INN), 巴他布林

+ [8]

Target

β-tubulin

Mechanism

β-tubulin inhibitors(Tubulin beta inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersNervous System Diseases+ [2]

Active Indication-

Inactive Indication

Breast CancerColorectal CancerGlioma+ [4]

Originator Organization

Amgen, Inc.

Active Organization-

Inactive Organization

Tularik, Inc.

Amgen, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC13H7F6NNaO3S

InChIKeyRRFNAEBCEOAASM-UHFFFAOYSA-N

CAS Registry195533-98-3

View All Structures (2)

Gene Sequence

Sequence Code 9827723

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.

Start Date01 Mar 2003

Sponsor / Collaborator

Tularik, Inc.

NCT00022243 / Unknown statusPhase 2

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.

Start Date01 Oct 2000

Sponsor / Collaborator

Tularik, Inc.

NCT00003359 / CompletedPhase 1IIT

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.

Start Date01 Apr 1998

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

[+1]

100 Clinical Results associated with Batabulin Sodium

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100 Translational Medicine associated with Batabulin Sodium

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100 Patents (Medical) associated with Batabulin Sodium

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8

Literatures (Medical) associated with Batabulin Sodium

01 May 2019·Journal of Biological ChemistryQ2 · BIOLOGY

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

Q2 · BIOLOGY

Article

Author: 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.

15 Jul 2009·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

Author: 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.

01 Jan 2005·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with Batabulin Sodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D06560	-	-	DB16103

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Unresectable Hepatocellular Carcinoma	Phase 3	PR	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	CN	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	US	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	UA	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	ZA	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	SG	Tularik, Inc.	01 Mar 2003
Unresectable Hepatocellular Carcinoma	Phase 3	TH	Tularik, Inc.	01 Mar 2003
Liver Cancer	Phase 3	US	-	-
Liver Cancer	Phase 3	-	-	-
Liver Cancer	Phase 3	-	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2005	Phase 2/3	Hepatocellular Carcinoma	339	T138067 250 mg/m2	(jlkzjbyhkl) = xsvopzehuo idjiofetxi (zguwoiassn )	Negative	01 Jun 2005
				DOX 60 mg/m2	(jlkzjbyhkl) = ykbklicujp idjiofetxi (zguwoiassn )