CN107638424B - Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicines for treating cancers - Google Patents

Abstract

The invention relates to application of an EGFR/HER2 receptor tyrosine kinase inhibitor in preparing a medicament for treating cancer. Specifically, the invention relates to an application of an EGFR/HER2 receptor tyrosine kinase inhibitor compound shown in formula (I) in preparation of a medicine for treating drug-resistant cancer with anti-HER 2.

Description

Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicines for treating cancers

Technical Field

The invention relates to application of an EGFR/HER2 receptor tyrosine kinase inhibitor in preparing a medicament for treating drug-resistant cancers resistant to HER 2.

Background

Breast cancer is one of the most common malignancies in women. According to the world health organization statistics, about 120 million women are diagnosed with breast cancer worldwide each year, and the incidence of breast cancer increases at a rate of 5% to 20% each year.

Its incidence is often genetically related and the incidence of disease is higher in women between the ages of 40-60 and before and after menopause. Only about 1-2% of breast patients are male. Malignant tumors usually occur in mammary gland epithelial tissues. Is one of the most common malignant tumors which seriously affect the physical and mental health of women and even endanger life.

Many factors are known to induce this disease, mainly the following: the age: in women, the incidence rate increases with age, rarely before the onset of menstruation and rarely before 20 years old, but after 20 years old, the incidence rate rapidly increases, is higher at 45-50 years old but relatively flat, and the incidence rate continuously increases after menopause and reaches the highest peak at about 70 years old. The mortality rate also increases with age, gradually increasing after age 25, and always keeping on the rising trend until the elderly; genetic factors: family women have a first-level family history of breast cancer, and the risk of breast cancer is 2-3 times that of normal people; ③ other breast diseases; fourthly, the age of menstruation at first tide: the risk of the disease of the people with the early morning age of 13 years old is 2.2 times of that of the people with the age of more than 17 years old; menopausal age: an increased risk for menopause older than 55 years of age compared to younger than 45 years of age; sixthly, the age of the first pregnancy: the risk is gradually increased along with the late birth age, and the risk of the late birth age is higher than that of the people without childbearing history at the age of 35 years; supplementing estrogen after menopause: long-term estrogen administration during menopause may increase the risk of breast cancer; eighty oral contraceptive; ninthly, food: especially a fat diet, can increase the risk of breast cancer; consumption of alcohol in the red, body weight gain may be an important risk factor for post-menopausal women to develop breast cancer.

Currently, the choice of treatment regimen and efficacy of breast cancer depends on a number of factors: operation treatment: surgical treatment is one of the main treatments for breast cancer, and the first treatment for those with lesions still confined to regional or regional lymph nodes is surgery. ② radiotherapy: in recent years, with the improvement of radiation equipment and technology and the progress of radiobiological research, the radiation can make local tumors obtain higher dose, and the surrounding normal tissues have less damage, so that the radiation treatment effect is obviously improved. ③ endocrine treatment: it is slower than chemotherapy, and often takes weeks to achieve remission. The efficacy of endocrine therapy is independent of endocrine function status, but related to tumor cell differentiation and hormone receptor status. Chemical drug therapy: breast cancer is one of the most effective tumors in solid tumors using chemotherapy, which plays an important role in the overall treatment.

The low-toxicity multi-target antitumor drug is the current trend of drug research and development. Receptor tyrosine kinases

ERBB2 belongs to the epidermal growth factor receptor (EGFR, ERBB) protein family. This family includes 4 receptors (ERBB1-4, also known as ERBB 1-4). ERBB family receptors are a class of transmembrane proteins involved in growth factor signaling, and they have similar topologies: the glycosylated extracellular domain is divided into a ligand binding domain, a hydrophobic single transmembrane domain, and an intracellular tyrosine kinase catalytic domain and a regulatory sequence. These receptors are expressed in many tissues, including epithelial cells, mesenchymal cells, and neural tissue. Under normal physiological conditions, its activation is tightly controlled by its ligand. After binding to the ligand, the receptor forms a homodimer or heterodimer, which then causes phosphorylation of some tyrosine residues in the cell. These phosphorylated residues serve as binding sites for recruitment of many functional proteins, activating downstream signaling pathways, including the MAPK pathway, PI3K-AKT pathway, and STAT pathway, among others. After ERBB is activated, a very broad range of cellular biological responses is produced, including differentiation, proliferation, invasion and metastasis. Their aberrant expression leads to a disturbed regulation of cell proliferation and thus to tumorigenesis. There is overexpression of one or more ERBB receptors in 60% of tumors, with ERBB2 being highly expressed in 20-30% of breast cancer patients. Patients with ERBB-positive tumors usually have a worse disease and a poor prognosis. The ERBB family receptors have thus become an important target for anti-tumor therapy.

Currently, the antitumor drug clinically targeting the ERBB2 receptor is mainly monoclonal antibody trastuzumab (ERBBceptin). Trastuzumab contains two specific antigen binding sites and can be combined with a membrane-proximal region of an extracellular region of an ERBB2 receptor. Through binding with ERBB2, the compound inhibits the binding of a receptor and a ligand or the formation of a dimer between the receptors to play a role. In addition to inhibiting kinase activity, trastuzumab can also act by mechanisms such as increasing receptor endocytosis, recruiting macrophages and monocytes to act on tumor cells, and the like. Trastuzumab is now used primarily in combination with first-line chemotherapy to treat metastatic breast cancer that highly expresses ERBB 2. Trastuzumab can effectively prolong the relapse-free survival period of a patient by combining with a chemotherapeutic drug, and can effectively inhibit metastasis of a tissue which is highly expressed with ERBB2 but has not been completely deteriorated. Trastuzumab is therefore now also used as an adjunct therapy for early breast cancer with high expression of ERBB 2.

Another therapeutic strategy, relative to monoclonal antibody drugs, acts by binding to the intracellular kinase domain of the receptor, inhibiting the kinase activity of the receptor and blocking signal transduction. Such drugs are known as small molecule Tyrosine Kinase Inhibitors (TKIs). The small molecule tyrosine kinase inhibitor can enter cells, directly bind to a kinase area of a receptor, and inhibit the kinase activity of the receptor to play a role. And thus is a more direct and effective treatment strategy. For example, for some activation mutations lacking the extracellular region of ERBB2, a small molecule tyrosine kinase inhibitor has shown significant advantages over monoclonal antibody drugs, and lapatinib has been used clinically to treat trastuzumab-resistant breast cancer patients. In addition, the small molecule tyrosine kinase inhibitor can be generally orally administered, and is more convenient to use clinically. In recent years, small molecule tyrosine kinase inhibitors have received increasing attention as compared to monoclonal antibody drugs, and have been greatly developed. The selective inhibitors of EGFR, Gefitinib (Gefitinib), Erlotinib (Erlotinib), and the EGFR and ErbB2 dual-target inhibitor Lapatinib (Lapatinib), are in turn approved by the FDA for marketing.

The compound (I) is a new generation of small molecule tyrosine kinase inhibitor. Gefitinib, erlotinib and lapatinib, which are now widely used clinically, are reversible tyrosine kinase inhibitors that act by binding competitively to the kinase domain by ATP. While compound (I) is a non-reversible tyrosine kinase inhibitor. The mechanism of action is to alkylate cysteine residues in the ATP binding pocket of the kinase covalently bound to it, thereby permanently inactivating it. The mechanism of action of the irreversible inhibitors determines that the inhibitors not only effectively inhibit the activity of the kinase, but also have more lasting action time. A further important feature of non-reversible ERBB inhibitors is their broad spectrum, which generally inhibits multiple ERBB receptors. Non-reversible inhibitors are also effective against mutations that are resistant to some reversible inhibitors, due to differences in mechanism of action. The results of in vitro studies of the compound HKI-272(Neratinib) of the pfeiffer company, now in clinical trials, show that it inhibits the resistant T790M mutant strain of EGFR 3-4 times as much as gefitinib; yet another non-reversible ERBB inhibitor, buerger invager, BIBW2992(Afatinib), also demonstrated good efficacy in tests against reversible inhibitor resistant transplants.

The compound (I) is used as a non-reversible inhibitor and has an inhibiting effect on EGFR and ERBB 2. The preclinical experiments of the medicine show that the medicine has excellent antitumor activity. We have reasoned that compound (I) would be expected to benefit more widely in the future for patients with tumors.

CN102471312B discloses a compound (chemical name is (E) -N- [4- [ [ 3-chloro-4- (2-pyridylmethoxy) phenyl ] amino ] -3-cyano-7-ethoxy-6-quinolinyl ] -3- [ (2R) -1-methylpyrrolidin-2-yl ] prop-2-enamide) represented by the following formula I, and discloses that it has a strong inhibitory effect on EGFR and HER2, and is expected to be useful for the treatment of cancers in which EGFR and HER2 are overexpressed,

CN102933574B discloses a series of pharmaceutically acceptable salts of compounds of formula (I). CN103974949B discloses a crystalline form of the dimaleate salt of the compound of formula I.

None of the above documents, however, discloses the use of compounds of formula I for the treatment of cancers that have failed or are resistant to treatment with anti-HER 2, let alone in combination with antibody drug conjugates having anti-HER 2 action.

Disclosure of Invention

The present inventors have surprisingly found that compound (I) or a pharmaceutically acceptable salt thereof has a surprising effect on the treatment of cancers that have failed or are resistant to treatment with anti-HER 2, and have completed the present invention.

The cancer of the invention may be HER2 positive. Specifically, cancers contemplated by the present invention include, but are not limited to, lung cancer, gastric cancer, liver cancer, colorectal cancer, breast cancer; non-small cell lung cancer or breast cancer is preferred.

The failure or resistance to treatment with anti-HER 2 in the present invention refers to the progression of the disease after treatment with anti-HER 2 drugs, wherein said anti-HER 2 drugs include, but are not limited to, trastuzumab, pertuzumab, lapatinib, lenatinib; also included are antibody conjugates formed using anti-HER 2 monoclonal antibody via a linker to a cytotoxic drug, such as trastuzumab or pertuzumab with various cytotoxic drugs such as DM1, DM4, MMAE, MMAF, and the like, linked via a linker. Such conjugates are currently marketed, for example, T-DM1, which is a cytotoxic drug DM1 linked to the antibody trastuzumab via an SMCC linker.

In a preferred embodiment of the invention said compound (I) is used in combination with an anti-HER 2 antibody cytotoxic drug conjugate (ADC), preferably the ADC is T-DM 1.

The compounds of formula (I) of the present invention may be used in the form of various pharmaceutically acceptable salts, such as hydrochloride, methanesulfonate, maleate, malate, benzenesulfonate, etc., preferably maleate, especially dimaleate.

The amount of compound (I) or a pharmaceutically acceptable salt thereof can be selected by those skilled in the art as desired, and in a preferred embodiment, is 0.1 to 20mg/kg, preferably 0.5 to 10mg/kg, based on the free base of compound (I).

The amount of ADC used may be from 0.1 to 10mg/kg, preferably from 0.2 to 5 mg/kg.

Drawings

FIG. 1 shows the therapeutic effect of compound (I), T-DM1 and a combination thereof on human breast cancer BT-474/T721 nude mouse subcutaneous transplantable tumors;

FIG. 2 shows the effect of Compound (I), T-DM1 and the combination on body weight in tumor-bearing nude mice.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1: curative effect of compound (I) and T-DM1 on subcutaneous transplantation tumor of Herceptin-resistant human breast cancer BT-474/T721 nude mouse alone or in combination

1. Test drug

Drug name and lot number: compound (I) is a yellow powder with a content of 98.8%, batch No. S0915100514; T-DM1, white lyophilized powder, specification 80 mg/bottle, lot number P07A 113010711.

The source of the drug is as follows: compound (I) is administered as its dimaleate salt, prepared according to the method disclosed in CN 102933574B; T-DM1 was prepared according to the method disclosed in CN 101087611A.

The preparation method comprises the following steps: preparing a compound (I) by using distilled water; dissolving T-DM1 in distilled water to obtain 20mg/ml solution, packaging at-80 deg.C, and diluting with 0.1% BSA physiological saline to obtain the final product.

2. Laboratory animal

BALB/cA-nude mice, 6-7 weeks old, purchased from Shanghai Ling Biotech, Inc. Producing license numbers: SCXK (Shanghai) 2013-0018; animal certification number 2013001814724. A breeding environment: SPF grade.

3. Experimental procedure

Nude mice were inoculated subcutaneously with human breast cancer BT-474/T721 cells, and after tumors grew to 100-250mm3, the animals were randomly grouped (D0). The dosage and schedule of administration are shown in table 1. Tumor volumes were measured 2-3 times a week, mice weighed, and data recorded. Tumor volume (V) was calculated as:

v-1/2 × a × b2 wherein a and b represent length and width, respectively.

T/C (%) - (T-T0)/(C-C0)100 where T, C is the tumor volume at the end of the experiment; t0, C0 are tumor volumes at the beginning of the experiment.

4. Results

Breast cancer BT-474 cell channel

After long-term treatment to

The drug resistance is named as BT-474/T721. The compound (I) (1.5, 5mg/kg, PO, QD × 21) dose-dependently inhibited the growth of subcutaneous transplantable tumors of BT-474/T721 nude mice with tumor inhibition rates of 43% and 75%, respectively, and with partial regression of 1/10 tumors in the 5mg/kg group; the tumor inhibition rate of T-DM1(3mg/kg, IV, D0) on BT-474/T721 is 59%, which indicates that T-DM1 is still sensitive to BT-474/T721. The combination of the compound (I) and T-DM1 has the advantages of increased tumor inhibition rate of 67 percent (1.5 mg/kg of the compound (I) and 13mg/kg of T-DM 13) and 85 percent (5 mg/kg of the compound (I) and 13mg/kg of T-DM 13). The tumor-bearing mice can well tolerate the medicaments, and symptoms such as weight loss and the like do not occur.

Claims (7)

1. The application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicine for treating the breast cancer with failure or drug resistance to HER2,

wherein the medicament for anti-HER 2 treatment is trastuzumab.

2. The use of claim 1, wherein said breast cancer is HER2 positive.

3. The use of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a cytotoxic agent conjugate of anti-HER 2 monoclonal antibody, wherein the anti-HER 2 monoclonal antibody of the cytotoxic agent conjugate of anti-HER 2 monoclonal antibody is trastuzumab, and wherein the cytotoxic agent of the cytotoxic agent conjugate of anti-HER 2 monoclonal antibody is selected from the group consisting of DM1, DM4, MMAE, and MMAF.

4. The use of claim 3, wherein the anti-HER 2 monoclonal antibody cytotoxic drug conjugate is T-DM 1.

5. The use according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, mesylate, maleate, malate and besylate salts.

6. The use according to claim 1, wherein the pharmaceutically acceptable salt is the maleate salt.

7. The use according to claim 1, wherein the pharmaceutically acceptable salt is the dimaleate salt.

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