WO2019196621A1 - Use of quinazoline compound in drug for treating cancers with egfrv3 activating mutation - Google Patents

Abstract

Provided is the use of a quinazoline compound in a drug for treating cancers with an EGFRv3 activating mutation. The quinazoline compound includes a quinazoline derivative of the structure of formula I (I) and a salt, prodrug, prodrug salt, solvate and hydrate thereof or a polymorph thereof. Compared to the prior art, the present invention has the following beneficial effects: 1) the quinazoline derivative (I) of the present invention and the pharmaceutical salt thereof have an unexpected efficacy on cancers mediated by EGFRv3 mutations, and have a better efficacy than that on similar cancers without this mutation, for example, cancers with EGFRV3 mutations, metastatic brain cancer, metastatic meningeal cancer, brain cancer and central nervous diseases, etc.; and 2) the quinazoline derivative (I) of the present invention and the pharmaceutical salt thereof can increase the effectiveness on similar cancers for EGFRv3 mutations, and can be selected for cancer patients with EGFRv3 mutations and can also reduce costs.

Description

Use of quinazoline compounds in the treatment of cancer drugs having EGFRv3 activating mutations Technical field

The present invention relates to the use of a quinazoline compound for the treatment of a cancer having an EGFRv3 activating mutation, and belongs to the field of biomedical technology.

Background technique

a quinazoline derivative having a cross-blood-brain barrier, the molecular formula C ₂₃ H ₂₁ F ₃ N ₄ O ₂ , the chemical name (R)-6-[(3,3-difluoro-1-methylpiperidine-4) -yl)oxy]-nitro-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I), is a molecularly targeted antitumor drug that has Highly selective epidermal growth factor receptor EGFR tyrosine kinase inhibitor for the treatment of non-small cell lung cancer brain metastases, meningeal metastasis, head and neck squamous cell carcinoma, squamous cell carcinoma, brainstem tumor, primary Brain cancer, glioma or other cancer. Chinese invention patent 201610982608.6 describes a preparation method and application of the above quinazoline derivative (I) (the molecular formula C ₂₃ H ₂₁ F ₃ N ₄ O ₂ ). As is known to those skilled in the art, a cancer patient of the same type with a particular genetic mutation will have a better response to the drug with this mutation, resulting in a better therapeutic effect. Therefore, it is important to study the efficacy of a drug against a specific mutation and to improve the efficacy of the drug in this type of cancer. It is very useful to select a specific patient and reduce the cost.

EGFR _V 3 (EGFRvIII) is a deletion gene for exons 2 to 7 of epidermal growth factor EGFR and does not allow the mutant receptor to bind to any known ligand. Abnormal signaling of EGFRvIII plays an important role in driving tumor progression and is often associated with poor prognosis. EGFRv3 mutations are expressed in brain cancer, glioma, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, head and neck squamous cell carcinoma, lung cancer, lung squamous cell carcinoma, ovarian cancer, prostate cancer, brainstem tumor, and the like. See, Terrance G. Johns et al, FEBS Journal 280 (2013) 5350-5370. There are currently no drugs available for EGFRv3 mutations.

Summary of the invention

In view of the deficiencies in the prior art, it is an object of the present invention to provide a use of a quinazoline compound for the treatment of a cancer having an EGFRv3 activating mutation.

The invention is achieved by the following technical solutions:

In a first aspect, the present invention provides the use of a quinazoline compound for the treatment of a cancer having an EGFRv3 activating mutation.

Preferably, the quinazoline compound comprises Formula I

Structure of quinazoline derivatives and salts, prodrugs, prodrug salts, solvates thereof, hydrates thereof or polymorphs thereof.

Preferably, the cancer having an EGFRv3 activating mutation comprises a glioma, a head and neck squamous cell carcinoma, a lung squamous cell carcinoma, a brain stem tumor, a primary brain cancer, and a breast cancer.

Preferably, the cancer having an EGFRv3 activating mutation comprises a glioma, a head and neck squamous cell carcinoma, a lung squamous cell carcinoma, a brain stem tumor, a primary brain cancer, a prostate cancer, and a breast cancer.

In a second aspect, the invention also provides a cancer drug for use in the aforementioned use comprising a quinazoline compound and / or one or more pharmaceutically acceptable excipients.

Preferably, the excipient comprises a solubilizer.

Pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, sucrose and glucose, starches such as potato starch and corn starch, cellulose and its derivatives such as sodium carboxymethylcellulose, cellulose acetate and Ethylcellulose, gelatin, tragacanth powder, talc, malt, cocoa butter and suppository wax, oil, for example, peanut oil, safflower oil, cottonseed oil, olive oil, sesame oil, corn oil and soybean oil, glycol, for example Polyethylene glycol and propylene glycol, esters, for example, ethyl oleate and ethyl laurate, agar, buffers, for example, magnesium hydroxide and aluminum hydroxide, alginic acid, Ringer's solution, isotonic saline, ethanol, phosphoric acid Salt buffer, non-toxic compatible lubricants, for example, sodium lauryl sulfate and magnesium stearate, colorants, coatings, release agents, sweeteners, flavoring and fragrances, antioxidants, preservatives, Ion exchange, alumina, lecithin, aluminum stearate, self-emulsifying drug delivery system (SEDDS) such as vitamin E polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tweens or the like a serum, such as human serum albumin, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, a salt or an electrolyte, for example, protamine sulfate, potassium hydrogen phosphate , disodium hydrogen phosphate, sodium chloride and zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyacrylates, waxes, and polyethylene-polyoxypropylene-block polymerization Things. Cyclodextrins, for example, alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin, or chemically modified derivatives, for example, hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl rings Dextrin or other solubilized derivative used to enhance delivery of the compounds described herein.

Compared with the prior art, the present invention has the following beneficial effects:

1) The quinazoline derivative (I) of the present invention and a pharmaceutically acceptable salt thereof have an unexpected pharmacological effect on a cancer mediated by an EGFR _V 3 mutation, and are better than a cancer of the same type without the mutation. Efficacy, such as cancer with EGFR _V 3 mutation, cancer brain metastasis, cancer meningeal metastasis, brain cancer and neurological diseases;

2) The quinazoline derivative (I) and the pharmaceutically acceptable salt thereof according to the present invention can increase the effectiveness against EGFR _V 3 mutations in the same type of cancer, and can be used for cancer patients having the EGFR _V 3 mutation to reduce the cost.

DRAWINGS

Other features, objects, and advantages of the present invention will become apparent from the Detailed Description of Description

Figure 1 is a graph showing the inhibitory effect of the quinazoline derivative (I) of the present invention on EGFRv3 phosphorylation;

2 is a pharmacological effect of the quinazoline derivative (I) of the present invention on a tumor-transplanted animal model of primary tumor tissue of a patient having an EGFRv3 mutation;

Figure 3 is a pharmacokinetic/pharmacodynamic parameter of a quinazoline derivative (I) of a tumor-transplanted animal model of a primary tumor tissue of a patient having an EGFRv3 mutation.

detailed description

The invention will now be described in detail in connection with specific embodiments. The following examples are intended to further understand the invention, but are not intended to limit the invention in any way. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the inventive concept. These are all within the scope of protection of the present invention.

Example 1

This example relates to the use of a quinazoline derivative (I) for inhibition of phosphorylation of EGFRv3 mutations

In western blot experiments, the cells were cultured to 2×10 ⁵ /mL, treated with the concentration of the compound described herein (0, 10, 100, 1000 nM) for 24 hours, the medium was discarded, buffer was added, and ultrasonically centrifuged. Electrophoretic separation, immunohybridization and color development, phosphorylation of EGFRv3 was inhibited by quinazoline derivatives (I). Figure 1 shows that quinazoline derivatives (I) have good biological activity and are specifically mediated by EGFRv3 phosphorylation. Cancer.

Example 2

This example relates to a tumor-transplanted animal model of a quinazoline derivative (I) in a primary tumor tissue of a subcutaneous mouse patient with a EGFRv3 mutant brain tumor.

The patient's primary tumor tissue (brain tumor) was implanted into the skin of the mouse, and the tumor began to be administered for about three weeks after the tumor grew to about 150 mm ³ .

In the tumor-implanting animal model drug experiment of a brain tumor with an EGFRv3 mutation in a mouse subcutaneous patient primary tumor tissue, the first group was a control group and did not contain any drug. The second group of quinazoline derivatives (I) single agent, 3 mg / kg, orally, twice a day, the third group of quinazoline derivatives (I) single agent, 10 mg / kg, oral, two a day Second, the fourth group of quinazoline derivatives (I) single agent, 20 mg / kg, orally, twice a day. The drug group (second, third, and fourth groups) showed a good inhibition of tumor growth compared with the first group (control group), with statistically significant pharmacological effects, showing dose-dependent drug efficacy in animal models, group 4 Tumor reduction, Figure 2 shows good efficacy. And statistically significant differences in efficacy. RNA sequencing of the tumor revealed a mutation in EGFRv3, indicating that the quinazoline derivative (I) has good biological activity and potency against the EGFRv3 mutation.

Example 3

In vitro inhibition of tissue cells in patients with EGFRv3 mutation

3.5 mL of 2 × 10 ⁵ /mL cells were mixed with 6.5 mL of 1 v/v% methylcellulose, and 90 μL was added to a 96-well plate and incubated overnight. On the first day, 10 μL of the number of cells was read, and cells were lysed by adding 100 μL of CellTiter-Glo reagent, and fluorescence was read using EnVision Multi Label Reader. Add different concentrations of compound (0.33, 1, 3.3, 10, 33, 100, 333, 1000, 3333, 10000 nM), after 7 days, add 100 μL

The reagent was lysed into each well and the fluorescence was corrected using EnVision Multi Label Reader to obtain inhibition of the cells.

Survival rate (%) = (drug concentration group test results - nutrient solution control test results) / (excluding drug concentration group test results - nutrient solution control test results) × 100%.

IC ₅₀ <100nM.

Example 4

Pharmacokinetic/pharmacodynamic parameters in a tumor-transplanted animal model of primary tumor tissue in patients with EGFRv3 mutation

In the drug pharmacokinetic/pharmacodynamic experiment of a tumor-transplanted animal model of a mouse tumor with a EGFRv3 mutation in a subcutaneous patient's primary tumor tissue, the patient's primary tumor tissue was implanted under the skin of a female BALB/c nude mouse, two After the month, the tumors grew to about 200-400 mm3 and were randomly divided into groups. The first group was the control group, and no drug (3) was taken orally. Tissue samples were taken. The second group of quinazoline derivatives (I) single agent, 5 mg / kg, once orally, take tissue samples and plasma after oral administration, 0.5 hours (3), 2 hours (3), 4 hours (3) , 8 hours (3), the third group of quinazoline derivatives (I) single agent, 20 mg / kg, once orally, take tissue samples and plasma after oral administration, 0.5 hours (3), 2 hours (3 ), 4 hours (3), 8 hours (3). The concentration of the drug in plasma was multiplied by the protein binding rate of the drug in plasma to obtain the drug free concentration (ng per ml) at each time point (0.5 hour, 2 hours, 4 hours, 8 hours). Immunofluorescence and color analysis were used to analyze the phosphorylation of EGFRVIII in the tissue control group to obtain total phosphorylation. The tissue samples were analyzed for phosphorylation of EGFRVIII at each time point in the treatment group, and the phosphorylation inhibition rate was obtained at each time point by the total phosphorylation of EGFRVIII in the control group. Construct a pharmacokinetic/pharmacodynamic PK/PD relationship map (Figure 3). It can be seen from the figure that the free concentration of drug in the 5 mg per kg dose group is 1.66 ng per ml, and the inhibition of EGFR VIII is about 41.3%. In the 20 mg per kg dose group, the drug free concentration is 22.4 ng per ml, inhibiting EGFRVIII by about 98.5%. , showing dose-dependent inhibition of EGFRVIII phosphorylation.

The specific embodiments of the present invention have been described above. It is to be understood that the invention is not limited to the specific embodiments described above, and various modifications and changes may be made by those skilled in the art without departing from the scope of the invention.

Claims (6)

1. Use of a quinazoline compound for the treatment of a cancer having an EGFRv3 activating mutation.
2. The use according to claim 1, wherein the quinazoline compound comprises

   

   Structure of quinazoline derivatives and salts, prodrugs, prodrug salts, solvates thereof, hydrates thereof or polymorphs thereof.
3. The use according to claim 1, wherein the cancer having an EGFRv3 activating mutation comprises a glioma, a head and neck squamous cell carcinoma, a lung squamous cell carcinoma, a brain stem tumor, a primary brain cancer, and a breast cancer.
4. The use according to claim 1, wherein the cancer having an EGFRv3 activating mutation comprises a glioma, a head and neck squamous cell carcinoma, a lung squamous cell carcinoma, a brain stem tumor, a primary brain cancer, a prostate cancer, and a breast cancer. .
5. A cancer drug for use according to claim 1, characterized in that it comprises a quinazoline compound and/or one or more pharmaceutically acceptable excipients.
6. The cancer drug according to claim 5, wherein the excipient comprises an excipient, a buffer, a lubricant, a coloring agent, a coating agent, a releasing agent, a sweetener, a flavoring agent, a fragrance, and an antioxidant. At least one of a preservative, an ion exchanger, a surfactant, and a solubilizer.

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