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New application of ibrutinib

A technology of ibrutinib and uses, applied in a new field of use of ibrutinib, can solve the problems of patient recurrence, low clinically tolerated dose of the drug, and poor selectivity of EGFR mutants, etc.

Inactive Publication Date: 2015-08-12
HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients treated with TKI inhibitors often face the dilemma of relapse due to the development of TKI resistance
The second generation of EGFR irreversible inhibitors such as Canertinib, Afatinib, Neratinib, Pelitinib, etc. have entered clinical trials, but these molecules have Poor selectivity of EGFR mutants leads to lower clinically tolerated doses of the drug
At present, there are no relevant reports on the use of ibrutinib (PCI-32765) in the treatment of patients with drug-resistant non-small cell lung cancer carrying EGFR T790M mutation and / or EGFR L858R mutation and / or EGFR delE746_A750 mutation

Method used

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  • New application of ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Effect of Ibrutinib (PCI-32765) on Cancer Cell Growth

[0042]By testing the effect of ibrutinib (PCI-32765) on cancer cell growth, we further evaluated the selectivity of ibrutinib (PCI-32765) in inhibiting cancer cell proliferation. In this example, we selected human non-small cell lung cancer cell NCI-H1975 (expressing EGFR L858R / T790M double mutant gene), human lung adenocarcinoma cell NCI-H3255 (expressing EGFR L858R mutant gene), mouse EGFR-T790M BaF3 cells (stable expression of TEL-EGFR-T790M activated mutant kinase), human non-small cell lung cancer cell PC-9 (expression of EGFR delE746_A750 mutant gene), human skin squamous cell carcinoma A431 (expression of wild-type EGFR gene), human non-small cell lung cancer cells Small cell lung cancer cell NCI-H460 (expressing wild-type EGFR gene), human lung adenocarcinoma cell A549 (expressing wild-type EGFR gene), human non-small cell lung cancer cell NCI-H358 (expressing wild-type EGFR gene). The above c...

Embodiment 2

[0046] Example 2: In vitro inhibitory activity (enzyme activity) of ibrutinib (PCI-32765)

[0047] The IC50 values ​​of ibrutinib (PCI-32765) on EGFR (WT), EGFR / T790M, and EGFR L858R / T790M were determined in the in vitro enzyme activity assay as described below. The intracellular segment (699-1068) of EGFR was cloned into the insect expression vector pAcG2T, using the insect expression system BaculoGold TM Protein expression was performed using the Baculovirus Expression System (BD Pharmingen) with a GST tag. At the same time, the T790M and L858R sites were mutated to obtain the T790M single mutation vector and the T790M / L858R double mutation vector of EGFR respectively. The constructed vector was transfected into the SF9 packaging virus, and the virus was used to infect the SF9 expression protein.

[0048] Take 9 μL (6 ng / μL) of purified EGFR (WT), EGFR (T790M), EGFR (T790M / L858R) protein kinase and react with three-fold serially diluted drugs WZ4002 and PCI-327651 μL at...

Embodiment 3

[0053] Embodiment 3: plate colony formation experiment

[0054] The NCI-H1975 human non-small cell lung cancer cells in the exponential growth phase carrying the EGFR L858R / T790M double mutation were made into a cell suspension by conventional trypsinization and passaging. Pipette the cell suspension repeatedly to fully disperse the cells. NCI-H1975 human non-small cell lung cancer cells carrying EGFR L858R / T790M double mutation were counted, and the cell concentration was adjusted with medium.

[0055] According to the proliferation ability of NCI-H1975 human non-small cell lung cancer cells carrying EGFR L858R / T790M double mutation, according to 10 5 The concentration of cells / well was inoculated into a six-well plate (4 cm in diameter) containing 2 mL of medium, and the culture plate was gently shaken in a cross direction to make the cells evenly dispersed.

[0056] Place the Petri dish at 37°C, 5% CO 2 After 24 hours of incubation in medium, the drug concentration was...

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Abstract

The invention discloses a new application of ibrutinib (PCI-32765). In particular, it is found that the ibrutinib can treat non-small cell lung cancer carrying EGFR T790M mutation and / or EGFR L858R mutation and / or EDFR delE746-A750 mutation, and especially, can treat the non-small cell lung cancer carrying double-mutation of EGFR L858R and EGFR T790M.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a new application of ibrutinib (PCI-32765). Background technique [0002] Lung cancer is a common clinical malignant tumor of the lung, generally divided into two categories: small cell lung cancer (Small Cell Lung Cancer, SCLC) and non-small cell lung cancer (Non-Small Cell Lung Cancer, NSCLC). The morbidity and mortality of lung cancer rank first among malignant tumors, among which non-small cell lung cancer accounts for the vast majority and is the most common. The incidence of non-small cell lung cancer is increasing year by year all over the world, which seriously threatens human health. Non-small cell lung cancer is the leading cause of cancer death in the United States, Japan, and Western European countries. For advanced patients, although chemotherapy can improve the survival rate to a certain extent, chemotherapy drugs also have significant toxicity to the human body, so there ...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61P35/00
CPCA61K31/519
Inventor 刘青松刘静王蓓蕾王傲莉吴宏胡晨王文超陈程王黎李希祥
Owner HEFEI INSTITUTES OF PHYSICAL SCIENCE - CHINESE ACAD OF SCI
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