Delving into the Latest Updates on Tasidotin Hydrochloride with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

SYN-D, Synthadotin, Tasidotin

+ [9]

Target

β-tubulin

Mechanism

β-tubulin inhibitors(Tubulin beta inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Solid tumor

Inactive Indication

Castration-Resistant Prostatic CancerLocally Advanced Lung Non-Small Cell CarcinomaLocally Advanced Melanoma

Originator Organization

Abbott Laboratories

Active Organization

The University of Texas Health Science Center At Tyler

ILEX Oncology, Inc.

Inactive Organization

Genzyme Corp.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC32H58N6O5.ClH

InChIKeyOOKIODJYZSVHDO-QMYFOHRPSA-N

CAS Registry623174-20-9

View All Structures (2)

Sequence Code 122039

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).

Start Date22 Oct 2009

Sponsor / Collaborator-

NCT00078455

/ CompletedPhase 2

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.

Start Date01 Dec 2003

Sponsor / Collaborator

Genzyme Corp.

100 Clinical Results associated with Tasidotin Hydrochloride

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100 Translational Medicine associated with Tasidotin Hydrochloride

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100 Patents (Medical) associated with Tasidotin Hydrochloride

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16

Literatures (Medical) associated with Tasidotin Hydrochloride

01 Oct 2013·Molecular and Cellular BiochemistryQ3 · BIOLOGY

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

Q3 · BIOLOGY

Article

Author: 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.

01 Oct 2009·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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.

01 Jul 2009·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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 Deals associated with Tasidotin Hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
D06009	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	US	ILEX Oncology, Inc.	01 Apr 2004
Solid tumor	Preclinical	US	The University of Texas Health Science Center At Tyler	01 Apr 2004
Castration-Resistant Prostatic Cancer	Discovery	US	Genzyme Corp.	04 May 2004
Locally Advanced Lung Non-Small Cell Carcinoma	Discovery	US	Genzyme Corp.	01 Dec 2003
Locally Advanced Melanoma	Discovery	US	Genzyme Corp.	01 Aug 2003

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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	Metastatic melanoma \| Locally Advanced Melanoma	65	ILX651 28mg/m2	(tsbvmjgzpe) = dnzoryxcnt nksgqvbhys (xcgxkyngqn ) View more	-	01 Jun 2005
ASCO2004	Phase 1	HR-positive/HER2-low Solid Tumors	93	SYN-D	(enmuvppqvn) = hgkrybiueu cokpyzfkdn (ejykppcznw ) View more	-	15 Jul 2004