Use of quinazolines in overcoming osimertinib resistance

Abstract

The present invention discloses the use of a quinazoline derivative represented by formula (I) and at least one of its salts, prodrugs, prodrug salts, solvates, hydrates, and crystalline polymorphs in overcoming osimertinib resistance, which belongs to the field of pharmaceutical and health technology. Cell experiments and kinase inhibition experiments have shown that the compound can overcome osimertinib resistance caused by EGFR C797S, L792H, Del19 / C797S double mutation, or L858R / C797S double mutation, providing a means for pharmaceutical and health use in treating non-small cell lung cancer and its central nervous system metastasis. [Formula 1] JPEG2025527834000006.jpg86118

Description

[Technical Field]

[0001] The present invention relates to the use of quinazoline compounds in overcoming osimertinib resistance and belongs to the field of biopharmaceuticals. [Background technology]

[0002] Quinazoline derivatives that cross the blood-brain barrier have the molecular formula C 23 H 21 F3N4O2, whose chemical name is (R)-6-[(3,3-difluoro-1-methylpiperidin-4-yl)oxy]-nitrogen-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I), is a molecular targeted antitumor drug and a highly selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and can be used to treat non-small cell lung cancer with brain or meningeal metastasis, head and neck squamous cell carcinoma, squamous cell carcinoma, brainstem tumor, primary brain tumor, glioma, or other cancers. Chinese Patent 201610982608.6 discloses the quinazoline derivative (I) (molecular formula C 23 H 21 The preparation method of F3N4O2 and its application are described. As those skilled in the art know, after treatment with osimertinib (also known as AZD9291, Tagrisso, Osimertinib, Tagrisso), drug resistance mutations occur, making osimertinib unable to effectively inhibit tumor growth. Therefore, the research and development of inhibitors that overcome drug resistance-causing mutations is very useful and of great significance. Summary of the Invention [Problem to be solved by the invention]

[0003] The present invention aims to provide a use (application) of a quinazoline compound in overcoming osimertinib resistance. [Means for solving the problem]

[0004] The present invention is achieved by the following solutions.

[0005] The present invention provides the use of a quinazoline compound in the manufacture of a medicament capable of overcoming osimertinib resistance.

[0006] In a preferred embodiment, the quinazoline compound includes at least one of a quinazoline derivative represented by Formula I and a salt, prodrug, prodrug salt, solvate, hydrate, or crystalline polymorph thereof. [ka]

[0007] In a preferred embodiment, the quinazoline compound includes hydrochloride, sulfate, maleate, succinate, adipate, glycolate, malate, fumarate, benzenesulfonate, benzoate, hippurate and oxalate salts of quinazoline derivatives, as well as solvates, hydrates and crystalline polymorphs.

[0008] In a preferred embodiment, the pharmaceutical agent is a pharmaceutical agent for treating non-small cell lung cancer resistant to osimertinib and central nervous system metastasis of non-small cell lung cancer.

[0009] In a preferred embodiment, the central nervous system metastasis of non-small cell lung cancer includes brain metastasis of non-small cell lung cancer or meningeal metastasis of non-small cell lung cancer.

[0010] In a preferred embodiment, the osimertinib resistance is caused by EGFR C797S, L792H, Del19 / C797S double mutation, or L858R / C797S double mutation. [Effects of the Invention]

[0011] Compared with the prior art, the present invention has the following beneficial effects:

[0012] 1. The quinazoline derivative (I) and its pharmaceutically acceptable salts described in the present invention can overcome osimertinib resistance, particularly resistance caused by EGFR C797S, L792H, Del19 / C797S double mutation or L858R / C797S double mutation, and inhibit tumor growth.

[0013] 2. The quinazoline derivative (I) and its pharmaceutically acceptable salts according to the present invention can effectively treat non-small cell lung cancer that is ineffective after treatment with osimertinib, as well as central nervous system metastasis of non-small cell lung cancer, including brain metastasis and meningeal metastasis of non-small cell lung cancer, and cancers caused by the above-mentioned resistance mutations. [Brief explanation of the drawings]

[0014] The features, objects and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings.

[0015] [Figure 1] This shows an experiment on the anti-cell proliferation biological activity of Ba / F3 L858R / C797S and Del19 / C797S with osimertinib as a control drug. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention will be described in detail below based on specific examples. The following examples are intended to help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any way. It should be noted that those skilled in the art may make some modifications and improvements without departing from the concept of the present invention, all of which fall within the scope of protection of the present invention. [Example]

[0017] Cytostatic effects of the quinazoline derivative (I) described in the present invention and the control drug osimertinib in Ba / F3 L858R / C797S and Del19 / C797S cell proliferation biological activity experiments

[0018] DMSO dilutions of drugs at different concentrations (0.05, 0.15, 0.45, 1.37, 4.11, 12.3, 37.0, 111.1, 333.3, and 1000 nM) were added to a 384-well microplate, and 30 μl of the cell suspension was dispensed into the microplate at a concentration of 700 μg / well. After incubating the cells at 37°C and 5% CO2 for 72 hours, 25 μl of CelltiterGlo reagent (CTG) was added, and the plate was shaken until uniform. After incubating at 37°C and 5% CO2 (protected from light) for 30 minutes, the fluorescent signal was read using an Envision. The IC was used as an index for evaluating anti-cell proliferation activity. 50 (50% maximal inhibitory concentration) and relative potency%, and the calculation formula is relative potency% = IC of osimertinib 50 / IC of quinazoline derivatives (I) 50 ×100%.

[0019] As shown in Figure 1, in inhibiting the cell proliferation biological activity of Ba / F3 L858R / C797S and Del19 / C797S, the quinazoline derivative (I) according to the present invention overcame osimertinib resistance and exhibited a higher inhibitory effect on cell proliferation caused by osimertinib-resistant mutant EGFR L858R / C797S and Del19 / C797S compared to osimertinib, with relative biological activity approximately 490-fold and 4900-fold higher than that of osimertinib.

[0020] [Table 1] [Example]

[0021] Inhibitory effects of the quinazoline derivative (I) described in the present invention and the control drug osimertinib on EGFR C797S, L792H, L858R / C797S and Del19 / C797S kinases

[0022] DMSO dilutions of drugs at different concentrations (0.017, 0.05, 0.15, 0.45, 1.37, 4.11, 12.3, 37.0, 111.1, and 333.3 nM) were added to a 384-well microplate. Five microliters (μl) of kinase, polypeptide substrate (TK-substrate-biotin), and ATP were added and incubated at room temperature for 40 minutes. Five microliters of Sa-XL665 HTRF detection buffer and TK-antibody-Cryptate were added and incubated at room temperature for 1 hour. Fluorescence signals were read at 615 nm (Cryptate) and 665 nm (XL665) using an Envision 2104 microplate reader. The IC was used to evaluate antikinase activity. 50 (50% maximal inhibitory concentration) and relative potency%, and the calculation formula is relative potency% = IC of osimertinib 50 / IC of quinazoline derivatives (I) 50 ×100%.

[0023] In biological activity experiments of inhibitory effects on EGFR C797S, L792H, L858R / C797S and Del19 / C797S kinases, the quinazoline derivative (I) according to the present invention overcame osimertinib resistance and exhibited a high inhibitory effect on osimertinib-resistant mutant EGFR C797S, L792H, L858R / C797S and Del19 / C797S kinases compared to osimertinib, with relative biological activities approximately >1052-fold, 49-fold, 93118-fold and 498-fold higher than those of osimertinib.

[0024] [Table 2]

[0025] The quinazoline derivative (I) described in the present invention overcomes osimertinib resistance and, compared with osimertinib, exhibits a high inhibitory effect on the osimertinib-resistant mutations EGFR C797S, L792H, L858R / C797S and Del19 / C797S. It can overcome the resistance caused by the EGFR C797S, L792H, Del19 / C797S double mutation or the L858R / C797S double mutation, inhibit tumor growth, and can effectively treat non-small cell lung cancer that is ineffective after treatment with osimertinib, central nervous system metastasis of non-small cell lung cancer, and cancers caused by the above-mentioned resistance mutations.

[0026] The specific embodiments of the present invention have been described above. The present invention is not limited to the above specific embodiments, and it should be understood that those skilled in the art can make various modifications and alterations within the scope of the claims without affecting the essential content of the present invention.

Claims

1. Use of quinazoline compounds in the manufacture of a drug capable of overcoming osimertinib resistance.

2. The quinazoline compound is 【Chemical 1】 2. The use according to claim 1, comprising at least one of a quinazoline derivative of formula (I) and its salts, prodrugs, prodrug salts, solvates, hydrates and crystalline polymorphs.

3. The use according to claim 2, characterized in that the salt of the quinazoline compound includes a hydrochloride, sulfate, maleate, succinate, adipate, glycolate, malate, fumarate, benzenesulfonate, benzoate, hippurate or oxalate salt of a quinazoline derivative, and the quinazoline compound further includes a solvate, hydrate or crystalline polymorph of the salt.

4. The use according to claim 1, wherein the medicament is a medicament for treating non-small cell lung cancer resistant to osimertinib and central nervous system metastases of non-small cell lung cancer.

5. The use according to claim 4, wherein the central nervous system metastasis of non-small cell lung cancer comprises brain metastasis of non-small cell lung cancer or meningeal metastasis of non-small cell lung cancer.

6. 2. The use according to claim 1, wherein the osimertinib resistance is caused by EGFR C797S, L792H, Del19 / C797S double mutation or L858R / C797S double mutation.

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