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Therapeutic combinations comprising a raf inhibitor and a erk inhibitor

A technology of inhibitors, kinase inhibitors, used in c-RAF inhibitors, ERK inhibitors, pharmaceutical compositions containing such combinations, therapeutic combinations for the treatment of cancer, in the field of cancer treatment, to address unmet medical needs, etc. question

Active Publication Date: 2019-05-03
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is a high unmet medical need for patients with KRAS-mutant NSCLC and patients with BRAF-mutant NSCLC

Method used

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  • Therapeutic combinations comprising a raf inhibitor and a erk inhibitor
  • Therapeutic combinations comprising a raf inhibitor and a erk inhibitor
  • Therapeutic combinations comprising a raf inhibitor and a erk inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0105] Example 1 : N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide

[0106] Compound A (Compound A) is a morpholine-substituted biaryl compound having the structure

[0107]

example 1

[0110] In vitro Raf activity assay

[0111] Both the RAF enzyme and the catalytically inactive MEK1 protein substrate were prepared in-house using conventional methods. The CRAF cDNA as a full-length protein (with Y340E and Y341E activating mutations) was subcloned into a baculovirus expression vector for Sf9 insect cell expression. The h14-3-3ζ cDNA was subcloned into a baculovirus expression vector for expression in SF9 insect cells. Sf9 cells co-expressing the two proteins were lysed and subjected to immobilized nickel chromatography, eluted with imidazole. A second column (StrepII binding column) was used and eluted with desthiobiotin. Protein tags are removed using Prescission enzyme and the protein is further purified using a flow-through step to remove tags.

[0112] C-Raf FL refers to full length C-Raf protein.

[0113] Full-length MEK1 with an inactivating K97R ATP-binding site mutation was used as a RAF substrate. Use the N-terminal (his) of MEK1 cDNA 6 Tags we...

example 1

[0136] Compound A exhibited activity in a number of human cancer cell lines expressing mutations in the MAPK pathway, as shown in the table below. Note that activity is particularly strong for cell lines with at least one mutation in BRAF or RAS.

[0137] Table 1. Effect of Compound A on the proliferation of a panel of human cancer cell lines.

[0138]

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Abstract

The present invention relates to a combination treatment which comprises (a) at least one ERK inhibitor preferably Compound B as described herein, and (b) a c-RAF inhibitor or a pharmaceutically acceptable salt thereof, preferably Compound A, which may be combined into a single pharmaceutical composition or prepared for separate or sequential administration. It includes a c-RAF inhibitor and an ERK inhibitor prepared for simultaneous, separate or sequential administration for the treatment of a proliferative disease, particularly an advanced solid tumor that harbors a Mitogen-activated proteinkinase (MAPK) alteration, and includes methods of using these compounds in combination as well as a commercial package comprising such combination.

Description

technical field [0001] The present invention relates to the use of inhibitors of RAF, in particular inhibitors of c-RAF (C-RAF or CRAF), for the treatment of cancers which are advanced solid tumors with altered mitogen-activated protein kinase (MAPK), such as KRAS - mutant tumors, and in particular KRAS-mutant NSCLC (non-small cell lung cancer), melanoma, pancreatic cancer, colorectal cancer and ovarian cancer. The present invention relates in particular to therapeutic combinations using at least one RAF inhibitor for the treatment of cancer. [0002] The present invention also relates to the use of ERK inhibitors (ERKi) for the treatment of cancers, in particular cancers with KRAS-mutations, and in particular gain-of-function mutations of KRAS, including lung cancer (in particular NSCLC), melanoma , pancreatic cancer, and ovarian cancer. [0003] The invention further relates to a pharmaceutical combination comprising (a) at least one ERK inhibitor (ERKi), and (b) a Raf inh...

Claims

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Application Information

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IPC IPC(8): A61K31/505A61K31/5377A61K45/06A61P35/00
CPCA61K45/06A61K31/505A61K31/5377A61P35/00A61K2300/00A61K9/0053A61K31/4965
Inventor G·卡波尼格罗M·J·迈尔V·库克D·斯图尔特
Owner NOVARTIS AG