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Combination drug therapy

A technology of compounds and combination products, applied in drug combinations, antineoplastic drugs, pharmaceutical formulations, etc.

Inactive Publication Date: 2016-04-27
GLAXO SMITHKLINE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Thus, although there have been many recent advances in the treatment of cancer with compounds such as the androgen receptor, there remains a need for more effective and / or enhanced treatments for individuals affected by cancer

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0290] Antiproliferative effects of compound A and compound B in prostate cancer cells

[0291] LNCaP prostate cancer cells are androgen receptor positive and depend on androgen for cell growth. Cells were grown in charcoal-stripped serum to remove potential androgens from the serum. Under these conditions, cell growth is dependent on exogenous androgens (eg, R1881). The androgen receptor antagonist Compound A inhibits the growth of LNCaP cells in a concentration-dependent manner in the presence of synthetic androgen (0.1 nMR1881). Similarly, Compound B also inhibited the growth of LNCaP cells under these conditions. When LNCaP cells were treated concomitantly with both compounds, there was an additive antiproliferative effect ( figure 1 ).

[0292] Cell Proliferation Assay

[0293] The androgen-dependent prostate cancer cell line LNCaP was cultured at a density of 1,000 cells / well in 96-well tissue culture plates for 24 hours in RPMI1640 medium supplemented with 10% ...

Embodiment 2

[0295] Effects of Compound A and Compound B on Cell Signaling in Prostate Cancer Cells

[0296] LNCaP cells were treated with compound B (3 or 10 uM) alone or in the presence of compound A (3 uM), both in the presence of 0.1 nM of synthetic androgen (R1881).

[0297] Compound B inhibits AKT phosphorylation, suggesting inhibition of PI3 kinase activity in cells. The AKT inhibitor used as a control in this experiment (it was either alone or in combination with compound A, also labeled ENZA) demonstrated a reduction in phosphorylation of downstream signaling as evidenced by a reduction in phospho-PRAS40 and phospho-S6 . Compound B treatment alone and in the presence of Compound A demonstrated inhibition of phospho-S6, a marker of downstream pathway regulation.

[0298] The combination of the two compounds resulted in a greater decrease in phospho-S6 levels compared to Compound B alone. Decrease in S6 phosphorylation has been associated with greater anti-proliferative effects...

Embodiment 3

[0302] Effects of Compound A and Compound B on Caspase 3 / 7 Induction in Prostate Cancer Cells

[0303] Caspase 3 / 7 activity, a marker of apoptosis, was measured using a luminescent caspase 3 / 7 assay in LNCaP cells treated with Compound A (5 uM), Compound B (5 uM), or both ). Caspase 3 / 7 activity was normalized and plotted as a percentage of untreated control samples. Data from 2 independent experiments (N=1, N=2) are shown and represent mean ± standard deviation from duplicate treatments.

[0304] In LNCaP cells, there was a slight induction of caspase 3 / 7 activity after 5 days of treatment with compound B or compound A, while treatment with the combination had a further increase (1.4-2.0 fold in growth medium, 2.5-4 times in culture medium)( image 3 ).

[0305] Luminescent caspase 3 / 7 assay

[0306]Tumor cells were inoculated in 100 μL of growth medium (medium containing 10% FBS) or CSS medium (medium containing 10% activated carbon-absorbed fetal calf serum) in 96-...

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Abstract

A novel combination comprising the androgen receptor inhibitor, 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide or a pharmaceutically acceptable salt or solvate thereof, with a PI3K[beta] inhibitor, 2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of androgen receptor and / or PI3K[beta] is beneficial, e.g., cancer.

Description

technical field [0001] The present invention relates to a method of treating cancer and combinations useful in such treatment. Specifically, the method involves the inclusion of the androgen receptor inhibitor 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioimidazolidin-1-yl)-2-fluoro-N-methylbenzamide or a pharmaceutically acceptable salt or solvate thereof and PI3Kβ inhibitor 2-methyl-1-{[2- Novel combinations of methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof, comprising Pharmaceutical compositions thereof, and methods of using such combinations and compositions in the treatment of conditions in which inhibition of the androgen receptor and / or PI3Kβ is beneficial, eg, cancer. Background technique [0002] Effective treatment of hyperproliferative disorders, including cancer, is an ongoing goal in the field of oncology. In general, cancer results from the dereg...

Claims

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Application Information

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IPC IPC(8): A61K31/4166A61K31/535C07D233/86C07D413/10
CPCA61K31/4166A61K31/535A61P35/00A61P35/02A61P35/04A61P43/00A61K2300/00A61K31/5377
Inventor J.格雷肖克K.E.巴赫曼S.C.布莱克曼
Owner GLAXO SMITHKLINE LLC