Inhibitors of Tubulin Polymerization

a technology of tubulin and polymerization, which is applied in the field of inhibition of tubulin polymerization, can solve problems such as failure of mitosis

Inactive Publication Date: 2006-12-07
RIGEL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If any of these stages of chromosomal alignment and separation is disrupted by irregular microtubules, mitosis fails.
Further, that lability is critical for their function.
Certain drugs exploit the necessity of tubulin free-exchange in mitosis and act therapeutically by disrupting the delicate balance between microtubule polymerization and depolymerization.

Method used

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  • Inhibitors of Tubulin Polymerization
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  • Inhibitors of Tubulin Polymerization

Examples

Experimental program
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Effect test

example 1

Inhibition of Tubulin Polymerization

[0087]FIG. 1 illustrates the inhibition of tubulin polymerization activity conferred by exemplary compounds of the invention.

[0088] The assay measures tubulin polymerization as an increase in turbidity (A340) over time. Assays for tubulin polymerization were performed using a kit from Cytoskeleton (Denver, Colo.) and as described by Tahir, S, K., et al, (2001) Cancer Res., 61: 5480-5, incorporated herein by reference, and as described below.

[0089] To determine the ability of the compounds to inhibit microtubule polymerization in vitro, the following protocol was followed: (i) 70 μl ice-cold MAP-rich tubulin protein from bovine brain (1.5 mg / ml final concentration) was added to polymerization buffer (80 mM PIPES pH6,8, 1 mM EGTA, 1 mM MgCl2, 1 mM GTP) in a quartz microcuvette; (ii) 0.7 μl of DMSO or 100× stock of control (nocodazole) or test compound (thienopyrimidine) in DMSO were added to the cuvette; (iii) the contents were mixed by pipetting...

example 2

Antitumor Activity of Compound 1 Against Human Lung and Colon Tumors in Nude Mouse Xenografts

[0090] A nude mouse / human carcinoma model was used to examine the effect of tubulin inhibitors on tumor growth and animal survival. Groups of immune deficient (nude) mice were implanted subcutaneously with suspensions of the human tumor lines A549 (lung) and SW480 (colon). When palpable tumors appeared and were of a preselected volume (approximately 40-150 mm3), animals were subdivided into various treatment groups such that the variation in mean tumor volume of each group was within 10%. The animals were then treated daily with either control vehicle or Compound 1 administered by intraperitonel injection. Twice weekly, the volume of the tumors in each animal in each group was measured to gather information on tumor growth (volume) as a function of time. Systemic toxicity was assessed by measuring individual animal body weights, and toxicity was evaluated by examination of differences in bo...

example 3

Bromodeoxyuridine (BrdU) Proliferation Assay

[0111] In order to determine the antiproliferative activity of microtubule inhibitors, A549 cells were plated in 96 well plates at 2000 cells / well 24 hours prior to the addition of a compound of the invention in 80 ul growth media (F12K, 10% FBS, Pen / Strep). Prior to addition to cells, compounds were solubilized in 100% DMSO to 5 mM and serially diluted in 6 semi-log steps in 100% DMSO. The diluted compounds were added to cells by two 15.8-fold dilution steps, the first being a dilution into a 23% ethanol / H20 mixture and the second being a dilution into growth media. Finally, these dilutions were followed by a 1:1 dilution onto cells. The resulting final solvent concentration was 0.2% DMSO / 0,75% ethanol. Compounds were tested at final concentrations of 10, 3, 1, 0.3, 0.1 and 0.03 uM. Forty-eight hours after the addition of compound, the effects on cellular proliferation were measured using a cell proliferation BrdU ELISA (Roche Molecular ...

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Abstract

The invention relates to the inhibition of tubulin polymerization. The invention provides compounds and methods for inhibiting tubulin polymerization. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Description

CROSS REFERENCE [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 369,223 filed Feb. 18, 2003 which claims priority to U.S. Provisional Application No. 60 / 357,560 filed Feb. 15, 2002.FIELD OF THE INVENTION [0002] This invention relates to the inhibition of tubulin polymerization. More particularly, the invention relates to compounds and methods for inhibiting the polymerization of tubulin. BACKGROUND OF THE INVENTION [0003] Microtubules are intracellular, filamentous, polymeric structures, present in eukaryotic cells, that extend throughout the cytoplasm and govern the location of membrane-bounded organelles and other cell components. Microtubules are involved in many cellular functions including chromosome migration during mitosis, organelle transport, cytokinesis, cell plate formation, cell motility, and maintenance of cell shape. Microtubules are composed of molecules of tubulin protein, each molecule of which is a heterodimer of α-tubulin and β-tub...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D495/04
CPCC07D495/04
Inventor GOFF, DANEBENNETT, MARKDEMO, SUSAN
Owner RIGEL PHARMA
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