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Combination of kinase inhibitors and uses thereof

a technology of kinase inhibitors and kinase inhibitors, which is applied in the field of kinase inhibitors, can solve the problems of undesirable effects on metabolic pathways and insulin signaling disruption, disrupt or reduce immune function, and reduce immune function, so as to effectively target disease-related pathways, inhibit undesirable side effects, and reduce the effect of immune function

Inactive Publication Date: 2015-03-26
INTELLIKINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]Due to the diverse essential functions of mTOR and PI3Ks, drugs that bind to and inhibit a broad range of kinase isoforms and complexes with low specificity can lead to deleterious side effects. For example, excessive inhibition of PI3K β may lead to undesirable effects on metabolic pathways and disruption of insulin signaling. Alternatively, excessive inhibition of PI3K δ and / or PI3K γ may disrupt or reduce immune function. The present disclosure provides an alternative approach that effectively targets disease-related pathways, while limiting undesirable side effects.

Problems solved by technology

Due to the diverse essential functions of mTOR and PI3Ks, drugs that bind to and inhibit a broad range of kinase isoforms and complexes with low specificity can lead to deleterious side effects.
For example, excessive inhibition of PI3K β may lead to undesirable effects on metabolic pathways and disruption of insulin signaling.
Alternatively, excessive inhibition of PI3K δ and / or PI3K γ may disrupt or reduce immune function.

Method used

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  • Combination of kinase inhibitors and uses thereof
  • Combination of kinase inhibitors and uses thereof
  • Combination of kinase inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Expression and Inhibition Assays of p110α / p85α, p110β / p85α, p1108 / p85α, and p110γ

[0966]Commercial kits or systems for assaying PI3-K activities are available. The commercially available kits or systems can be used to screen for inhibitors and / or agonists of PI3Ks including but not limited to PI3-Kinase α, β, δ, and γ. An exemplary system is PI 3-Kinase (human) HTRF™ Assay from Upstate. The assay can be carried out according to the procedures suggested by the manufacturer. Briefly, the assay is a time resolved FRET assay that indirectly measures PIP3 product formed by the activity of a PI3-K. The kinase reaction is performed in a microtiter plate (e.g., a 384 well microtiter plate). The total reaction volume is approximately 20 ul per well. In the first step, each well receives 2 ul of test compound in 20% dimethylsulphoxide resulting in a 2% DMSO final concentration. Next, approximately 14.5 ul of a kinase / PIP2 mixture (diluted in 1× reaction buffer) is added per well for a final co...

example 2

Expression and Inhibition Assays of Abl

[0967]The cross-activity or lack thereof of one or more compounds of the present invention against Abl kinase can be measured according to any procedures known in the art or methods disclosed below. For example, the compounds described herein can be assayed in triplicate against recombinant full-length Abl or Abl (T315I) (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg / mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.

example 3

Expression and Inhibition Assays of Hck

[0968]The cross-activity or lack thereof of one or more compounds of the present invention against Hck kinase can be measured according to any procedures known in the art or methods disclosed below. The compounds described herein can be assayed in triplicate against recombinant full-length Hck in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg / mL BSA. The optimized Src family kinase peptide substrate EIYGEFKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.

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Abstract

The present invention provides for a method for treating a disease condition associated with PI3-kinase α and / or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and / or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3-kinase α and / or mTOR in a subject.

Description

CROSS-REFERENCE[0001]This application is a continuation-in-part of PCT / US2012 / 026399 filed Feb. 23, 2012, published as WO 2012 / 148540, which claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 61 / 446,016, filed on Feb. 23, 2011, each incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Kinase signaling pathways play a central role in numerous biological processes. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al., Current Medicinal Chemistry (2007) 14:2214-2234). In recent years, kinases that are associated with oncogenic signaling pathways have emerged as important drug targets in the treatment of various diseases including many types of cancers.[0003]The mammalian target of rapamycin (mTOR), also known as mechanistic target of rapamyc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/551A61K31/519A61K31/4745A61K31/527A61K31/501A61K31/53A61K31/541A61K31/517A61K31/5377A61K31/498
CPCA61K31/551A61K31/5377A61K31/519A61K31/4745A61K31/498A61K31/501A61K31/53A61K31/541A61K31/517A61K31/527A61K2300/00A61K31/4439A61K45/06A61P11/00A61P13/12A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P43/00A61K31/4709A61K9/0053
Inventor REN, PINGDALIU, YIJESSEN, KATAYOUNGUO, XINROMMEL, CHRISTIANWILSON, TROY EDWARD
Owner INTELLIKINE
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