Tubulin-binding compounds, compositions and uses related thereto

a technology of tubulin and compound, applied in the field of compound, can solve problems such as important dose-limiting toxicities

Inactive Publication Date: 2018-12-13
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]Another aspect of this disclosure provides methods for treating a skin cancer in a subject in need thereof using a compound described herein. In some embodiments, the skin cancer that may be treated by a compound described herein is a melanoma. In some embodiments, the melanoma is selected from, but not limited to, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma, melanoma with small nevus-like cells, melanoma with features of a Spitz nevus, and uveal melanoma.

Problems solved by technology

Although microtubule-targeting agents are some of the most common chemotherapeutic agents used to treat a wide variety of cancers, they show important dose-limiting toxicities, including neutropenia and neurotoxicity, largely a consequence of disturbing microtubule dynamics in neurons.

Method used

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  • Tubulin-binding compounds, compositions and uses related thereto
  • Tubulin-binding compounds, compositions and uses related thereto
  • Tubulin-binding compounds, compositions and uses related thereto

Examples

Experimental program
Comparison scheme
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example 1

Synthetic Protocols

[0186]Chemistry: General Experimental Procedures.

[0187]All reagents and solvents were purchased from commercial suppliers and used without further purification unless otherwise stated. The reactions were monitored by thin layer chromatography (TLC) on precoated silica gel F254 plates (Sigma-Aldrich) with a UV indicator using chloroform:methanol (9.5:0.5 v / v). Yields were of purified product and were not optimized. The purity of the newly synthesized compounds was determined by LCMS analysis. The proton nuclear resonance (1H NMR) spectra were performed on a Varian GEMINI 2000 NMR spectrometer system with working frequency 400 MHz. Chemical shifts (δ) are given in ppm, and the following abbreviations are used: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad singlet (br s). All LCMS data were gathered on an Agilent 1100 LC system. The compound solution was injected into the ionization source (APCI) operating positive and negative modes wi...

example 2

-Activity Relationship Studies for Certain Compounds of the Invention

[0208]The cell viability IC50 of each compound was determined using Promega CellTiter-Glo Luminescent Cell Viability Assay kit by measuring the total ATP levels to quantify the number of metabolically active cells upon drug treatment as described in Crouch et al., J Immunol Methods 1993, 160, (1), 81-8. Briefly, the compounds were suspended in DMSO at 10 mM and diluted in 384 plates (20 μl / well in DMSO) in triplicate by a 14-point titration (12 nM to 100 μM). 50 μl of HeLa cells or patient derived glioblastoma cells (HK-309) (2000 cells / well) were then treated with the prepared dilutions of the drugs (0.5 μl) and incubated at 37° C. and 5% CO2. 72 hours later 50 μl of CellTiter-Glo reagent was added to each well followed by a 2 minutes shaking and a 10-minute incubation to lyse the cells. The relative luminescent intensity units (RLU) of each well was measured using a Tecan M1000 microplate reader (Tecan Group Ltd....

example 3

le Polymerization Assays

[0211]To further validate that compound 10 and its analogues were targeting microtubules, in vitro microtubule polymerization reactions were performed with the most potent compounds (10-10b) using the HTS-tubulin polymerization assay kit from Cytoskeleton Inc. Briefly, tubulin polymerization assays were conducted using the HTS-Tubulin polymerization assay kit from Cytoskeleton Inc. The reactions were carried out according to the manufacturer instructions (Cytoskeleton, BK011P) in the presence of 3 μM of test compounds (10, 10a, and 10b) and controls (DMSO, colchicine and taxol). 1.5 ul of 10X strength compound, 20 μl of tubulin solution and Triton X-100 at a final concentration of 0.01% were added to each well in a 384 well plate. The reactions were assembled on ice to prevent tubulin pre-polymerization. For kinetic measurements, microtubule polymerization was monitored by reading the fluorescence at 420 nm (due to the incorporation of a fluorescent reporter ...

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Abstract

This disclosure relates to antimitotic compounds, compositions comprising therapeutically effective amounts of these compounds, and methods of using those compounds and compositions in treating hyperproliferative disorders, e.g., cancers and myelodysplastic syndromes.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application is a U.S. National Stage of International Patent Application No. PCT / US2016 / 034286, filed May 26, 2016, which claims the benefit of U.S. Provisional Patent Application No. 62 / 167,526, filed May 28, 2015, and U.S. Provisional Patent Application No. 62 / 191,738, filed Jul. 13, 2015, the contents of each of which are fully incorporated by reference herein in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with Government support under TR000124 and CA016042, awarded by the National Institutes of Health. The Government has certain rights in the invention.FIELD OF THE DISCLOSURE[0003]This disclosure relates to compounds useful in compositions and methods for treating hyperproliferative disorders, including cancers.BACKGROUND OF THE INVENTION[0004]The cell cycle is a set of coordinated events that culminate in the formation of two cells from one mother cell. It is composed of ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D495/04A61P35/00
CPCC07D495/04A61P35/00C07D417/06C07D471/04C07D487/04C07D277/64
Inventor TORRES, JORGEDAMOISEAUX, ROBERTYEATES, TODD O.SENESE, SILVIAMCNAMARA, DAN E.LO, YU-CHEN
Owner RGT UNIV OF CALIFORNIA
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