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Combination therapy

A phenyl and benzyloxy technology, applied in the field of combination therapy, can solve problems such as poor prognosis

Pending Publication Date: 2018-10-23
NUCANA PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patients diagnosed with advanced (metastatic or unresectable locally advanced disease) biliary tract cancer have a poor prognosis

Method used

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  • Combination therapy
  • Combination therapy
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0192] Example 1 - Single Diastereomer of NUC-1031

[0193] The (R) and (S) isomers can be separated by HPLC under the following conditions:

[0194] Equipment: Agilent 1200 with DAD detector TM series

[0195] Flow rate: 1.0mL / min

[0196] Column: Chiralpak AD TM ;250×4.6mm ID (positive phase)

[0197] Temperature: Ambient

[0198] Particle size: 20μm

[0199] Feed: soluble in methanol; 10g / L

[0200] Solvent: n-heptane / IPA10->50% isopropanol

[0201] Chromatograms such as figure 1 shown. The (S)-epimer eluted at 8.6 minutes and the (R)-epimer at 10.3 minutes.

[0202] Characterization methods and materials: Protons were recorded at 25°C on a Bruker Avance500 spectrometer ( 1 H), carbon ( 13 C), phosphorus ( 31 P) and fluorine ( 19 F) NMR spectrum. Spectra are automatically calibrated to deuterated solvent peaks, all 13 C NMR and 31 P NMR homogeneous proton decoupling. Using Varian Polaris C18-A (10 μM) as the analytical column, using H from 100 / 0 to 0 / 100 w...

Embodiment 2

[0217] Example 2 - In vitro study of NUC-1031 and cisplatin combination.

[0218] 2.1 Materials and methods

[0219] Cell Culture and Reagents

[0220] A2780, SK-OV-3, OVCAR-3, NCI-H460, NCI-H1975, NCI-H2122, 5637 and HT1376 in RPMI medium 1640 (Invitrogen-10099141) supplemented with 10% fetal bovine serum (FBS; Invitrogen-10099141) 22400105) in culture. Keep all cell lines at 37°C, 5% CO 2 in a humid incubator. Cell culture media and supplements were purchased from Invitrogen, tissue culture flasks were purchased from Corning, and 96-well and 384-well plates were purchased from Greiner. The CellTiter-Glo Luminescent Cell Viability Assay Kit was purchased from Promega (Promega-G7573), the cell counter Vi-Cell was purchased from Beckman, and the detection instrument Envision was purchased from PerkinElmer. Paclitaxel (used as reference) and cisplatin were purchased from SELLECK with the highest purity. All compounds were soluble in DMSO and when diluted into media. DMS...

Embodiment 3

[0270] Example 3 - Further in vitro studies of the combination of NUC-1031 and cisplatin

[0271] Cell Culture and Reagents

[0272] SKOV3 cells were purchased from the American Type Culture Collection (ATCC). Place them in a 10% Gibco TM FBS (Life Technologies; 10270-106) and 1% Gibco TM Penicillin-Streptomycin (Life Technologies; 15140122) Gibco TM RMPI Medium 1640+GlutaMAX TM -I (Life Technologies; 61870-010) (called complete medium), at 37°C, 5% CO 2 Cultured in cell culture flasks. Cisplatin was purchased from TEVA UK Limited (PL 00289 / 1146). Fluvastatin and Sulforaphane were both purchased from Merck Millipore Corporation (catalog numbers 344096 and 574215, respectively). (S)-NUC-1031 by Ltd provided.

[0273] Cell culture for drug application

[0274] SKOV3 cells were plated at 250 cells in 200 μl per well on In the middle 60 wells of the 3596 96-well plate, each well of the outer 36 wells was filled with 200 μl of PBS. Cells were grown in complete med...

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Abstract

This invention relates to a combination of gemcitabine-[phenyl-benzoxy-L-alaninyl)]- phosphate (chemical name: 2'-Deoxy-2',2'-difluoro-D-cytidine-5'-O-[phenyl (benzoxy- L- alaninyl)] phosphate) (NUC-1031) and a platinum-based anticancer agent selected from cisplatin, picoplatin, lipoplatin and triplatin. The combinations are useful in the treatment of cancer and particularly biliary tract and bladder cancer.

Description

[0001] The present invention relates to gemcitabine-[phenyl-benzyloxy-L-alanyl)]-phosphate (chemical name: 2'-deoxy-2',2'-difluoro-D-cytidine-5'-O - a combination of [phenyl(benzyloxy-L-alanyl)]phosphate) (NUC-1031 ) and a platinum-based anticancer agent selected from the group consisting of cisplatin, Picoplatin, lipoplatin and triplatin. Background technique [0002] NUC-1031 [0003] Gemcitabine (1; as marketed) is a potent nucleoside analog currently approved for the treatment of breast, non-small cell lung, ovarian and pancreatic cancers and widely used for the treatment of a variety of other cancers including bladder cancer, bile duct cancer, colorectal cancer and lymphoma. [0004] [0005] The clinical utility of gemcitabine is limited by a number of intrinsic and acquired resistance mechanisms. At the cellular level, drug resistance depends on three parameters: (i) downregulation of deoxycytidine kinase (which is required for activation into the phosphorylated ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7068A61P35/00A61K33/00A61K33/243
CPCA61K31/282A61K31/44A61K31/7068A61P35/00A61K33/243A61K2300/00A61K33/24A61K9/0019
Inventor 休·格里菲斯
Owner NUCANA PLC
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