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

a technology of bcl-2 family proteins and quinoline derivatives, which is 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 cos

Inactive Publication Date: 2015-06-04
EUTROPICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about methods and compounds for treating cancer and autoimmune diseases involving Bcl-2 family proteins. The invention is based on the discovery of methods and compounds that can manipulate Bcl-2 family proteins, which are involved in regulating the cell's fate. The invention provides methods of using compounds of Formula I, II, or III for treating various disease states, including cancer and autoimmune diseases. The compounds have specific structures and scaffolds that make them useful for treating these diseases. The technical effects of the invention include the development of new methods and compounds for treating cancer and autoimmune diseases, as well as identifying common substructures or scaffolds that can be used for developing new treatments.

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of Mcl-1 by Compounds of Formula I-III

[0297]In this example, a Fluorescence Polarization (FP) assay was used to demonstrate the activity of the Mcl-1 inhibitors described in Formulas I-III 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.

[0298]A nineteen amino acid peptide, corresponding to the BH3 domain of Bim, with the sequence FITC-GGGIAQELRRIGDEFNAY (SEQ ID NO: 14) was labeled with the fluorophore FITC according to the manufacturer's instructions (Molecular Probes, Eugene, Oreg.). This sequence was identified as being able to bind to purified Bcl-xL protein (Sattler et al. (1997) Science 275(5302): 983-86, which is hereby incorporated by reference in its entirety) and to have biological activity in cells (Holinger et al. J. Biol. Chem. 274: 13298-1330, which is hereby incorporated by reference in its entirety).

[0299]In addition, recombinant GST-Mcl-1 and GST-Bcl-xL fusion proteins were gene...

example 2

Activity of Compounds of Formulae I, II, or III in Killing Mouse and Human Tumor Cell Lines

[0302]This example demonstrates the activity of the compounds of Formula I-III and derivatives, in killing certain human tumor-derived cell lines grown in culture. Leukemia and myeloid cells used to assess cell tumor killing activity of the compounds are described. Compounds active in these cell lines have good potential as therapies to treat leukemia and myeloid cancers.

Materials and Method

[0303]Cell Culture

[0304]The lymphoid derived cell lines DHL-6, DHL-8, and DHL-10 were obtained from Anthony Letai of the Dana Farber Cancer Research Institute, Boston, Mass. The myeloid derived cell line NCI-H929 was obtained from the NIH / NCI cell repository. The mouse leukemia-derived cell line MCL-1-1780 (Ryan et al., Proc. Nat. Acad. Sci USA, 107, 12895-12900, which is hereby incorporated by reference in its entirety) was obtained from Anthony Letai of the Dana Farber Cancer Research Institute, Boston, M...

example 3

Fluorescence-based cell-based cytotoxicity assay using 4′-6-diamidino-2-phenylindole (DAPI)

[0309]Materials and Methods

[0310]The mouse leukemia-derived cell lines Mcl-1-1780 and Bcl-2-1863 (Ryan et al., Proc. Nat. Acad. Sci USA, 107, 12895-12900, which is hereby incorporated by reference in its entirety) were obtained under license from Dana Farber Cancer Institute. Cells were grown in RPMI 1640 medium (GIBCO-BRL) with 2 mM L-glutamine, 4.5 g / L glucose, 1.0 mM sodium pyruvate and 5% fetal bovine serum. Cells were expanded in tissue culture in appropriate media and then sub-cultured into 96-well plates at a seeding density of 20,000 cells per well. After incubation for 24 hours, cells were treated with compounds that are titrated into appropriate medium with FCS. Four concentrations of compound were used: 1 μM, 500 nM, 250 nM, and 125 nM. Assay was run in triplicate for each compound at each concentration and averages were calculated. Cells were treated with compound for 24 hours, the...

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Abstract

The present invention relates to compositions and methods for cancer treatment comprising compounds of Formulae I, II, and III. In some aspects, the invention relates to the treatment of B-cell Lymphoma or other hematopoietic cancers. In other aspects, the invention provides methods for treating particular types of hematopoietic cancers, such as, for example, B-cell lymphoma, using a combination of one or more compounds of Formulae I, II, and III. Combination therapy with, for example, 26S proteasome inhibitors, such as, for example, Bortezomib, are also included. In another aspect the present invention relates to autoimmune treatment with compounds of Formulae I, II, and III. In another aspect, this invention relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and claims the benefit of U.S. Provisional Patent Application No. 61 / 662,084, filed Jun. 20, 2012, the entirety of which is incorporated herein by reference.GOVERNMENT SUPPORT[0002]Research leading to this invention was funded in part by SBIR grant number 1 R43CA 135915-01 from the National Cancer Institute, National Institutes of Health, Bethesda, Md.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY[0003]The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: EUTR—009—01WO_SeqList_ST25.txt, date recorded: Jun. 20, 2013, file size 4 kilobytes).FIELD OF THE INVENTION[0004]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.[0005...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496G01N33/50A61K45/06A61K38/05A61K31/454
CPCA61K31/496A61K38/05A61K31/454G01N2500/04G01N33/5011G01N33/5079G01N2500/10A61K45/06A61K31/4709A61K31/573A61K31/69A61K31/5377A61P35/00A61K2300/00G01N2333/82
Inventor CARDONE, MICHAEL H.RICHARD, DAVID J. J
Owner EUTROPICS PHARMA
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