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Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor

a technology of bcl-2 inhibitor and inhibitor, which is applied in the field of combination of btk inhibitor and btk inhibitor, can solve the problems that e.g. chemotherapy and the treatment of tumor cells themselves have not been sufficient to overcome the protective effect of the microenvironmen

Inactive Publication Date: 2017-08-17
ACERTA PHARMA BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides pharmaceutical combinations of a Bruton's tyrosine kinase (BTK) inhibitor, a BCL-2 inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and an anti-coagulant or antiplatelet active pharmaceutical ingredient. These combinations may be used to treat cancer, particularly B-cell lymphoma, and may provide improved efficacy and reduced side effects compared to using single agents alone. The combinations may also include a BTK inhibitor, a BCL-2 inhibitor, a PI3K inhibitor, and an anti-coagulant or antiplatelet active pharmaceutical ingredient.

Problems solved by technology

Addressing the tumor cells themselves with e.g. chemotherapy has also proven to be insufficient to overcome the protective effects of the microenvironment.

Method used

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  • Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
  • Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor
  • Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

ic Combination of a BTK Inhibitor and a PI3K-δ Inhibitor

[1855]Ficoll purified mantle cell lymphoma (MCL) cells (2×105) isolated from bone marrow or peripheral blood were treated with each drug alone and with six equimolar concentrations of a BTK inhibitor (Formula XVIII) and a PI3K-δ inhibitor (Formula IX) ranging from 0.01 nM to 10 μM on 96-well plates in triplicate. Plated cells were then cultured in HS-5 conditioned media at 37° C. with 5% CO2. After 72 hours of culture, cell viability was determined using an (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay (Cell Titer 96, Promega). Viability data were used to generate cell viability curves for each drug alone and in combination for each sample. The potential synergy of the combination of the BTK inhibitor of Formula XVIII and the PI3K-δ inhibitor of Formula IX at a given equimolar concentration was determined using the median effect model as described in Chou T C, Talalay P. ...

example 2

ic Combination of a BTK Inhibitor and a PI3K-δ Inhibitor

[1857]Combination experiments were performed to determine the synergistic, additive, or antagonistic behavior of drug combinations using the Chou / Talalay method / algorithm by defining combination indexes for drug combinations. Information about experimental design for evaluation of synergy is described in e.g. Chou T C, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 1984, 22, 27-55 and more generally in e.g.: Greco, W. R., Bravo, G., Parsons, J. C. The search for synergy: a critical review from a response surface perspective. Pharmacol. Rev. 1995, 47, 331-385. The study was performed using the BTK inhibitor of Formula XVIII and the PI3K-δ inhibitor of Formula IX. Single agent activities were first determined in the various cell lines and subsequently, the combination indexes were established using equimolar ratios taking the single ag...

example 3

ic Combination of a BTK Inhibitor and the JAK-2 Inhibitor Ruxolitinib

[1860]Combination experiments were performed to determine the synergistic, additive, or antagonistic behavior of drug combinations using the methods described above in Example 2. The study was performed using the BTK inhibitor of Formula XVIII and the JAK-2 inhibitor of Formula XXX (ruxolitinib).

[1861]The detailed results of the cell line studies for the BTK inhibitor of Formula XVIII and the JAK-2 inhibitor of Formula XXX (ruxolitinib) are given in FIG. 38 to FIG. 65. The results of the cell line studies are summarized in Table 4.

TABLE 4Summary of results of the combination of a BTKinhibitor with a JAK-2 inhibitor (S = synergistic,A = additive, X = no effect).Cell LineIndicationED25ED50ED75ED90RajiBurkitt'sSSSSRamosBurkitt'sSSSSDaudiBurkitt'sSSSSMinoMCLSSSSPfeifferiNHLSSSSDOHHiNHLSSSSREC-1iNHLSSSSJVM-2CLL likeSSSXU937MyeloidXXXXK562CMLXXXXSU-DHL-1ABCSSSSSU-DHL-2ABCSSSXHBL-1ABCSSSSTMD8ABCSSSSLY19GCBXXXXLY7GCBXXXXLY...

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Abstract

Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and / or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 62 / 035,795 filed on Aug. 11, 2014; U.S. Provisional Application No. 62 / 088,240 filed on Dec. 5, 2014; U.S. Provisional Application No. 62 / 115,497 filed on Feb. 12, 2015; and U.S. Provisional Application No. 62 / 181,160 filed on Jun. 17, 2015, all of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]Therapeutic combinations of a Bruton's tyrosine kinase (BTK) inhibitor, a B-cell lymphoma-2 (BCL-2) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and / or a Janus kinase-2 (JAK-2) inhibitor, and uses of the therapeutic combinations, are disclosed herein. In particular, a combination of a BCL-2 inhibitor and a BTK inhibitor and uses thereof are disclosed.BACKGROUND OF THE INVENTION[0003]PI3K kinases are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-OH group on phosphatidylino...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4985A61K39/395A61K31/454A61K31/635A61K31/519A61K31/52
CPCA61K31/4985A61K31/519A61K31/52A61K31/454A61K31/635A61K39/3955A61K45/06A61K31/437A61K31/4468A61K31/675A61P35/00A61K2300/00
Inventor HAMDY, AHMEDROTHBAUM, WAYNEIZUMI, RAQUELLANNUTTI, BRIANCOVEY, TODDULRICH, ROGERJOHNSON, DAVEBARF, TJEERDKAPTEIN, ALLARD
Owner ACERTA PHARMA BV
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