Combinations of cdk4/6 inhibitor lee011 and mek1/2 inhibitor trametinib, optionally further comprising pi3k inhibitor byl719 to treat cancer

A technology of cancer and preparations, applied in the field of treatment or prevention of cancer, α-isoform-specific phosphatidylinositol 3-kinase inhibitor compounds, capable of solving problems such as functional loss

Inactive Publication Date: 2018-06-08
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring and thus antagonizes PI3K activity, is functionally absent in many tumors

Method used

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  • Combinations of cdk4/6 inhibitor lee011 and mek1/2 inhibitor trametinib, optionally further comprising pi3k inhibitor byl719 to treat cancer
  • Combinations of cdk4/6 inhibitor lee011 and mek1/2 inhibitor trametinib, optionally further comprising pi3k inhibitor byl719 to treat cancer
  • Combinations of cdk4/6 inhibitor lee011 and mek1/2 inhibitor trametinib, optionally further comprising pi3k inhibitor byl719 to treat cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1: Combination of the CDK4 / 6 inhibitor LEE011 (also known as "ribociclib") with the MEK inhibitor trametinib and the PIK3CA inhibitor BYL719 (also known as "alpelisib") in a colorectal cancer cell (CRC) line In vitro effects on proliferation.

[0184] To test the effect of the combination of LEE011, trametinib and BYL719 on cell proliferation, cells were seeded in 50 μL of culture medium in black 384-well microplates with a clear bottom (Matrix / Thermo Scientific, catalog number 4332) / per well, the cell density is 500-1250 cells / well (Table 1), and at 37 degrees, 5% CO 2 Incubate for 24 hours. After 24 hours, 384-well plates / cell lines were prepared for cell counts by microscopy (see below) without treatment (='baseline). Additional cell plates were processed as follows: 25 nL of 2000X compounds were transferred from the drug master template using an ATS Acoustic Liquid Dispenser (ECD Biosystems) and a final 1X concentration was obtained. BYL719 was used in a...

Embodiment 2

[0188] Example 2: In vitro effect of combination of CDK4 / 6 inhibitor LEE011 and MEK inhibitor trametinib on proliferation in colorectal cancer cell (CRC) lines.

[0189] In order to test the effect of the combination of LEE011 and Trametinib on cell proliferation, the cells were seeded in 50 μL of medium / well in a black 384-well microplate (Matrix / Thermo Scientific, catalog number 4332) with a clear bottom, and the cell density was 500-1250 cells / well (Table 1), and at 37 degrees, 5% CO 2 Incubate for 24 hours. After 24 hours, 384-well plates / cell lines were prepared for cell counts by microscopy (see below) without treatment (='baseline). Additional cell plates were processed as follows: 25 nL of 2000X compounds were transferred from the drug master template using an ATS Acoustic Liquid Dispenser (ECD Biosystems) to obtain a final 1X concentration. LEE011 was used in a final concentration range of 13 nM-10 μM and trametinib was used in a final concentration range of 0.4 nM-...

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Abstract

The present disclosure relates to pharmaceutical combinations comprising a cyclin dependent kinase 4 / 6 (CDK4 / 6) inhibitor compound, (b) a mitogen activated protein kinase (MEK) inhibitor compound, andoptionally (c) an alpha-isoform specific phosphatidylinositol 3-kinase (PI3K) inhibitor compound, for the treatment or prevention of cancer, as well as related pharmaceutical compositions, uses, andmethods of treatment or prevention of cancer.

Description

technical field [0001] The present disclosure relates to a pharmaceutical combination comprising a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor compound, (b) a mitogen-activated protein kinase (MEK) inhibitor compound, and optionally (c) an alpha - Isoform-specific phosphatidylinositol 3-kinase (PI3K) inhibitor compounds for use in the treatment or prevention of cancer. The present disclosure also provides related pharmaceutical compositions, applications and methods for treating or preventing cancer. Background technique [0002] Tumor development is closely associated with genetic variation and dysregulation of cyclin-dependent kinases (CDKs) and their regulators, suggesting that CDK inhibitors may be useful anticancer therapies. In fact, early results suggest that transformed cells differ from normal cells in their requirements for e.g. cyclin D / CDK4 / 6 and may lead to the development of novel antineoplastic agents not observed with conventional cytotoxic and cytostatic...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K31/4439A61P35/00
CPCA61K31/4439A61K31/519A61P1/18A61P35/00A61P35/02A61P43/00A61K2300/00A61K31/496
Inventor G·卡波尼格罗T·霍恩-斯皮隆J·莱哈尔
Owner NOVARTIS AG
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