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Combination therapy involving diaryl macrocyclic compounds

A compound, immunotherapy technology, used in refrigeration and liquefaction, medical preparations containing active ingredients, heating methods, etc., can solve problems that have not yet caused successful treatment, etc.

Pending Publication Date: 2022-08-05
TURNING POINT THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Overall, pharmacological targeting of central downstream signaling effectors of mutant-activated RAS proteins has been challenging and has not resulted in clinically successful treatments

Method used

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  • Combination therapy involving diaryl macrocyclic compounds
  • Combination therapy involving diaryl macrocyclic compounds
  • Combination therapy involving diaryl macrocyclic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0600] In some embodiments, the methods described herein relate to cancer treatment comprising administering to a patient in need of treatment a therapeutically effective amount of one or more compounds that inhibit FAK, SRC and / or JAK2, and trametinib. In some embodiments, the methods described herein relate to cancer treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound that inhibits FAK, SRC and JAK2, and trametinib. It is to be understood that an inhibitor is one that reduces or inhibits the activity of another substance, such as a cell surface receptor (ie, receptor tyrosine kinase) or kinase (ie, non-receptor tyrosine kinase), or the transcription and / or transcription of a gene. or any substance translated. It will be appreciated that a "compound that inhibits FAK, SRC and JAK2" is a compound that has affinity for all three biological targets FAK, SRC and JAK2.

[0601] It has been discovered that certain o...

example 1

[0668] Example 1: NSCLC cell viability assay

[0669] One to two thousand cells per well were seeded in 96 or 384 well white dishes and then treated with the indicated compounds for 72-120 hours (37°C, 5% CO 2 ). Cell proliferation was measured using the CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufacturer's protocol. IC was performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA) 50 value determination.

[0670] exist Figure 1a Cells displaying a MEK1 / 2 inhibitor (trametinib), Compound 1, and a combination of a MEK1 / 2 inhibitor (trametinib) and Compound 1 (1 μM) in a mutant KRAS NSCLC cell line are shown in -1x Vitality % results. IC 50 The values ​​are summarized in Table 1. Although Calu-1, COR-L23, HCC1588, LCLC-97TM1, LU2512, NCI-H1155, NCI-H1373, NCI-H1573, SK-LU-1 and SW1573 NSCLC cell lines endogenously express KRAS mutations, MEK inhibitors Trametinib exhibited weak to undetectable inhibition of cell proliferat...

example 2

[0674] Example 2. Apoptosis analysis

[0675] Two thousand cells per well were seeded in 384-well white dishes and then treated with compounds for 24 or 48 hours (37°C, 5% CO 2 ). use The 3 / 7 Assay (Promega) followed the manufacturer's protocol to measure cellular caspase-3 / 7 activity (a major marker of apoptosis). exist Figures 1a-1d Shown in NSCLC cell lines with KRAS G12C mutations (H358, H2122), KRAS Q61H mutations (Calu-6), and KRAS G12V mutations (H441), in NSCLC cell lines with trametinib (50 nM), compound 1 ( 1 μM) and trametinib (50 nM) in combination with Compound 1 (1 μM) for 24 and 48 hours of treatment, results of increased caspase-3 / 7 activity. Compound 1 alone caused a modest increase in caspase-3 / 7 activity in NCI-H358, NCI-H2122 NSCLC cell lines after 48 hours of treatment ( Figure 1a , 1c ). Trametinib alone increased caspase-3 / 7 activity in H358, Calu-6, H2122 NSCLC cell lines after 48 hours of treatment ( Figures 1a-1c ). Compared to trametinib ...

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Abstract

The present disclosure relates to the use of diaryl macrocycles in conjunction with MAPK / ERK kinase-1 and 2 (MEK1 and MEK2; the present invention relates to methods and compositions for the treatment of cancer using combinations of inhibitors of MAP2K1 and MAP2K2, such as trametinib.

Description

technical field [0001] The present disclosure relates to methods and compositions for treating cancer with combinations of diaryl macrocycles with inhibitors of MAPK / ERK kinases-1 and -2 (MEK1 and MEK2; MAP2K1 and MAP2K2), such as trametinib . Background technique [0002] The Kirsten rat sarcoma virus oncogene homolog KRAS is one of three RAS protein family members (N, H, and K-RAS), which are small membrane-bound intracellular GTPase proteins. KRAS cycles between an inactive guanosine diphosphate (GDP) bound state and an active guanosine triphosphate (GTP) bound state. Active GTP-bound KRAS interacts with numerous effectors to stimulate multiple signaling pathways (eg, PI3K-AKT-MTOR, RAF-MEK-ERK), thereby affecting a range of cellular processes (eg, survival, proliferation, cytoskeletal organization). [0003] KRAS is one of the most frequently mutated oncogenes in a broad range of human cancers (18%, Catalog of Somatic Mutations in Cancer (COSMIC) database v90), includi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B60H1/32F24F5/00F25B23/00
CPCA61K31/529A61K31/4184A61K31/506A61K31/497A61K31/166A61K45/06A61P35/00A61K31/519A61K2300/00
Inventor 邓维翟大勇L·罗东B·W·默里景荣·J·崔N·V·李
Owner TURNING POINT THERAPEUTICS INC
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