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Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives

a family protein and bcl-2 technology, applied in the field of methods and compositions for treating cancer and autoimmune diseases, can solve the problems of blocking the sensitivity of tumor cells to cytostatic or apoptosis inducing drugs, poor survival prognosis of patients with cll, and high cost of treatmen

Inactive Publication Date: 2016-02-11
EUTROPICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to methods and compounds for treating cancer and autoimmune diseases, particularly hematological malignancies, by targeting Bcl-2 family proteins. The invention involves the use of compounds that inhibit the Bcl-2 family protein Mcl-1, as well as other BH3-mimics that target specific proteins. The invention also includes methods for predicting the selectivity of BH3 mimics for treating hematological malignancies. Overall, the invention provides new methods and compounds for treating cancer and autoimmune diseases by targeting Bcl-2 family proteins.

Problems solved by technology

CLL patients have a poor survival prognosis with a five-year survival rate of 46%.
In many cancers, anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Mcl-1, unfortunately block the sensitivity of tumor cells to cytostatic or apoptosis inducing drugs.
However, to date there are no conclusive reports from the clinic on the efficacy of any anti-cancer drug with this mode of action.
While pharmacological manipulation of the Bcl-2 family proteins is a feasible approach to achieving therapeutic benefit for cancer patients, the complexity of the network of proteins that comprise this family makes this prospect difficult.

Method used

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  • Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives
  • Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives
  • Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of Mcl-1 by Compounds of Formula I or Formula II; Measurement by ELISA Assay

[0253]The expression level of Mcl-1 correlates directly to chemo-sensitivity and survival of certain non-Hodgkin's lymphomas (Petlickovsk, et al. (2005) Blood 105(12): 4820-7) as well as prostate cancer (Royuela, et al. (2001) Eur. Cytokine Netw. 12(4): 654-63), liver cancer (Fleischer, et al. (2006) Int. J. Oncol. 28(1): 25-32) and other cancers. Mcl-1 is therefore an ideal target for treating these cancers. This example shows that the BH3 mimic compounds of Formula I or Formula II inhibit the binding of the BH3 domain of the Bcl-2 family protein Bim to Mcl-1. Accordingly, this example indicates that compounds of Formula I or Formula II are effective in treating certain hematological malignancies that are affected principally by the Bcl-2 family protein Mcl-1.

Materials and Methods

[0254]An ELISA-like streptavidin plate assay was used to demonstrate the activity of the BH3 mimic compounds of Formul...

example 2

Inhibition of Mcl-1 and Bcl-xL by Compounds of Formula I or II; Measurement by Fluorescence Polarization Assay

[0259]In this example, a Fluorescence Polarization (FP) assay is used to demonstrate the activity of the Mcl-1 inhibitors described in Formulas I or II in inhibiting Mcl-1 as well as Bcl-xL binding to Bim BH3 as described in Degterev et al. (2001) Nature Cell Biology 3: 173-182.

[0260]A nineteen amino acid peptide, corresponding to the BH3 domain of Bim, with the sequence FITC-GGGIAQELRRIGDEFNAY (SEQ ID NO: 1) is labeled with the fluorophore FITC according to the manufacturer's instructions (Molecular Probes, Eugene, Oreg.). This sequence is identified as being able to bind to purified Bcl-xL protein (Sattler et al. (1997) Science 275(5302): 983-86) and to have biological activity in cells (Holinger et al. J. Biol. Chem. 274: 13298-1330).

[0261]In addition, recombinant GST-Mcl-1 and GST-Bcl-xL fusion proteins are generated in E. coli and purified using glutathione-sepharose be...

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Abstract

The present invention relates to a compositions for and methods for cancer treatment, for example, hematopoietic cancers (e.g. B-cell Lymphoma). In other aspects, the invention provides methods for treating particular types of hematopoietic cancers, such as B-cell lymphoma, using a combination of one or more of the disclosed compounds and, for example, 26S proteasome inhibitors, such as, for example, Bortezomib. In another aspect the present invention relates to autoimmune treatment with the disclosed compounds. In another aspect, this invention relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have unique in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease.

Description

PRIORITY[0001]The present application claims priority to U.S. Provisional Application No. 61 / 729,251, filed on Nov. 21, 2012, the contents of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]This invention relates generally to methods and compositions for treating cancer and autoimmune diseases. Cancer may include hematological malignancies, such as Multiple Myeloma and B-cell lymphoma.BACKGROUND[0003]Currently the prevalence of Multiple Myeloma is 63,000 people in the U.S. with about 13,000 new cases per year. There are 360,000 cases of non-Hodgkin's lymphoma (NHL) in the United States and 550,000 worldwide, with about 56,000 cases diagnosed per annum and 23,000 deaths per annum (See American Cancer Society, SEER CANCER STATISTICS REVIEW 1975-2009 (Vintage 2009 Populations)). Twenty percent of these do not respond to current therapy. In terms of all NHL cases, 60% are aggressive, of which 50% do not respond to front line therapy. In additio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61K31/454A61K31/496A61K31/573A61K31/69A61K45/06
CPCA61K31/5377A61K45/06A61K31/496A61K31/573A61K31/454A61K31/69A61K31/4709A61K31/4725A61P35/00
Inventor RICHARD, DAVIDCARDONE, MICHAEL H.
Owner EUTROPICS PHARMA
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