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Inhibitors of the fibroblast growth factor receptor in combination with cyclin-dependent kinase inhibitors

A technology of growth factor receptors and fibroblasts, which is applied in the field of cancer treatment of subjects, and can solve the problems of lack of kinase selectivity and toxicity

Inactive Publication Date: 2019-07-16
BLUEPRINT MEDICINES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lack of kinome selectivity can lead to toxicity due to off-target effects

Method used

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  • Inhibitors of the fibroblast growth factor receptor in combination with cyclin-dependent kinase inhibitors
  • Inhibitors of the fibroblast growth factor receptor in combination with cyclin-dependent kinase inhibitors
  • Inhibitors of the fibroblast growth factor receptor in combination with cyclin-dependent kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0253] 1. A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one fibroblast growth factor receptor 4 (FGFR4) inhibitor and at least one cyclin-dependent kinase ( combination of CDK) inhibitors.

[0254] 2. The method of embodiment 1, wherein said at least one CDK inhibitor is selected from CDK4 / 6 inhibitors.

[0255] 3. The method of embodiment 1 or 2, wherein said at least one CDK inhibitor is selected from the group consisting of palbociclib, 7-cyclopentyl-N,N-dimethyl-2-((5-(piperciclib Azin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, 2-(2-chlorophenyl)-5,7-dihydroxy- 8-[(3S,4R)-3-Hydroxy-1-methyl-4-piperidinyl]-4-benzopyrone, N-(5-((4-ethylpiperazin-1-yl )methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl)-1H-benzo[d]imidazol-6-yl)pyrimidine-2 -Amines, GZ38-1 and pharmaceutically acceptable salts thereof.

[0256] 4. The method according to a...

Embodiment 1

[0309] Example 1: Combination studies of palbociclib and compound 1 in cells

[0310] Combinations of FGFR4 and CDK4 / 6 inhibitors were evaluated in several signal-seeking cell-based in vitro assays (data not shown). Use a variety of different standard antiproliferative assays such as MTS, MTT, and Cell Titer to filter. Many of the cell lines tested showed sensitivity, including in some cases partial responses, such as ZR-75-1, SW1116, TE-8, SNU-761, SNU-878, or in some cases synergistic Reactions such as JHH7, MDA-MB-453, Huh-7. Not all cell lines exhibit sensitivity, which may be due to various reasons. For example, lack of sensitivity is observed in cell lines that are resistant to either agent alone, such as cell lines that do not have an intact FGFR4 signaling pathway (eg, JHH4). In other cell lines, limitations related to the in vitro assay format or readout time points may affect activity. As previously reported, palbociclib activity may be weak in short-term ass...

Embodiment 2

[0315] Example 2: Growth Inhibition of Cells Treated with Palbociclib and / or Compound 1

[0316] Huh-7 cells were treated with the indicated concentrations of Compound 1, Palbociclib, or the combination of Compound 1 and Palbociclib for 72 hours. After compound incubation, Edu was added to the medium at a final concentration of 10 μM for 2 hours. Cells were then harvested and washed with 1% BSA in PBS to pellet the cells and resuspended in 100 μL of Click-iT TM Fixative (Invitrogen, Click-iT TM Plus EdU Flow Cytometry Assay Kit). Cells were incubated with fixative for 15 minutes at room temperature in the dark. Then, wash the cells as previously described and resuspend them in 100 μL 1XClick-iT TM Saponin-based permeabilization-wash reagent and incubate with the reagent at room temperature for 15 minutes in the dark. Then, add 500 μL Click-iT TM Plus reaction mix, incubate cells at room temperature for 30 minutes in the dark. Then, with 3mL 1XClick-iT TM Saponin-Ba...

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Abstract

Described herein are selective inhibitors of FGFR4, pharmaceutical compositions including such compounds, and combinations with other therapeutic agents, such as CDK inhibitors (e.g., CDK4 / 6 inhibitors), and methods of using such combinations.

Description

[0001] priority claim [0002] This application claims priority to U.S. Provisional Application No. 62 / 385,121, filed September 8, 2016, and U.S. Provisional Application No. 62 / 385,117, filed September 8, 2016, each of which is incorporated herein by reference in its entirety . Background technique [0003] Fibroblast growth factor receptor 4 (FGFR4) is a protein encoded by the FGFR4 gene in humans. This protein is a member of the fibroblast growth factor receptor family, and the amino acid sequence among members of this family is highly conserved throughout the evolutionary process. The ligand affinity and tissue distribution of FGFR family members 1 to 4 differ from each other. A representative full-length protein consists of an ectodomain composed of three immunoglobulin-like domains, a single hydrophobic transmembrane segment, and a cytoplasmic tyrosine kinase domain. The extracellular part of the protein interacts with fibroblast growth factor, initiates a series of do...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K9/00A61K31/4523A61K31/506A61K31/517A61K31/519A61P35/00A61P3/06
CPCA61K9/2004A61K31/4523A61K31/506A61K31/517A61K31/519A61K45/06A61P35/04
Inventor N·斯特斯基C·温特M·哈格尔K·霍夫里奇C·兰格L·徐
Owner BLUEPRINT MEDICINES
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