阅读说明：本技术 一种治疗白血病的药物 (Medicine for treating leukemia ) 是由 苗玉迪 于 2019-07-15 设计创作，主要内容包括：本发明涉及一种治疗白血病的药物,其具体包括一种化合物与多肽,该药物能提高白血病细胞的膜通透性以及细胞杀伤效果,并且其对正常细胞毒性低,因此能够有效抑制白血病细胞的细胞增殖、诱导肿瘤细胞凋亡,具有较好的应用前景。(The invention relates to a medicament for treating leukemia, which particularly comprises a compound and polypeptide, can improve the membrane permeability and the cell killing effect of leukemia cells, has low toxicity to normal cells, can effectively inhibit the cell proliferation of the leukemia cells and induce the apoptosis of tumor cells, and has better application prospect.)

1, SEQ ID NO: 1 permeation peptide and application of compound of formula 1 in preparation of drugs for treating leukemia

2. Use according to claim 1, characterized in that: wherein the dosage ratio of the medicines is as follows: 80 μ M polypeptide plus 20 μ M compound of formula 1.

3. Use according to claim 2, characterized in that: other drugs for inhibiting the migration, invasion and proliferation of leukemia cells are also added.

4. Use according to any one of claims 2 to 3, characterized in that: comprises pharmaceutically acceptable auxiliary materials which are compounded to prepare the medicinal composition.

5. The use of claim 3, wherein the medicament comprises a platinum antineoplastic agent.

6. The use according to claim 5, wherein the antineoplastic drug is cisplatin or carboplatin.

7. A cell membrane-permeable peptide, the sequence of which is as shown in SEQ ID NO: 1 is shown.

8. Use of the permeablin peptide of claim 7 in the preparation of a medicament for treating leukemia.

Technical Field

The invention relates to a medicine capable of specifically inhibiting leukemia, and belongs to the field of biological pharmacy.

Background

Leukemia (leukemia) is a malignant tumor disease that occurs in hematopoietic organs, with proliferation and dysplasia of leukocytes and their precursor cells in the blood and bone marrow. Due to abnormal differentiation of hematopoietic stem cells, leukemia cells abnormally excessively proliferate in bone marrow and other hematopoietic tissues, accumulate and infiltrate other tissues and organs, and inhibit normal hematopoiesis, and clinically present with symptoms of hemorrhage, anemia, infection and infiltration of various organs.

According to relevant statistics, leukemia accounts for about 3% of the incidence rate of tumors, and is better for children and young people, and male patients are more female than female patients. The incidence of leukemia is highest in countries around the world, both in europe and north america, with a mortality rate of 3.2-7.4 per 10 million people. Asia and south America have low morbidity with mortality rates of 2.8-4.5 per 10 million of the population and increasing at a rate of at least 3-4 million per year. The mortality rates of malignant tumors in the age groups of China are 6 th (male) and 8 th (female), respectively, and the mortality rates of children and children under 35 years old are 1 st.

In recent years, with the rapid development of economy in China, the environmental pollution is increasingly serious, tumors become the first diseases of China threatening the health and life of people, particularly the incidence rate of malignant tumors is continuously increased, and the condition of leukemia is not optimistic.

Leukemia can be classified into acute and chronic types according to the degree of maturation and the natural course of the leukemia cells. Acute leukemia is a malignant clonal hematological disease of hematopoietic stem and progenitor cell origin. Clinically, infection, hemorrhage, anemia and extramedullary tissue and organ infiltration are the main manifestations, and the disease progresses rapidly. The natural course of disease is only weeks to months. They can be generally classified into Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) according to their classification into leukemia cell series.

Chronic leukemia is characterized by hyperproliferation of functional differentiated mature cells, and chronic leukemia is therefore a disease due to poor signaling or uncontrolled cell proliferation, rather than to a failure of maturation. Chronic leukemia is usually chronic myelogenous leukemia (C ML) and Chronic Lymphocytic Leukemia (CLL).

The proliferation and infiltration of leukocytes are the specific pathological changes of leukemia, manifesting as lymphadenectasis, hepatosplenomegaly, and sternal tenderness. It can also be indicated for other infiltrations, such as pleural effusion, peritoneal or pericardial effusion, and central nervous system infiltration. Leukemia causes a decrease in the number and functional defects of neutrophils, which easily causes various bacterial infections, among which inflammation of the oral cavity, the intestine, the lung and the like is the most common. Thrombocytopenia, fibrinolysis, disseminated intravascular coagulation and plasma protein-bound polysaccharide increase, blood coagulation inhibition, and bleeding of patients, which are commonly seen in skin mucosa, hematopoietic tissue, spleen and stomach. The normal differentiated cells of the part produced by leukemia inhibit the normal hematopoietic cells, destroy the bone marrow environment for the growth of red blood cells, cause hemolysis and cause anemia. Leukocytosis can also lead to small vessel occlusion and hemorrhagic embolism, causing paralysis, coma, and even death of the patient.

Chemotherapy is still the main treatment for leukemia, and aims to eliminate leukemia cell clone and rebuild normal hematopoietic function of bone marrow. Acute leukemia treatment can be divided into two phases, induction remission and post-remission treatment (consolidation strengthening and maintenance treatment). The induction remission stage is a combined composition scheme of several different drugs with different mechanisms of action, and the dosage is to achieve the degree of mild inhibition of bone marrow. The medicine is taken for 1-2 courses of treatment to achieve complete relief and restore the hematopoietic function. But at the moment, the patient is not cured, the treatment enters the stage 2, namely post-remission treatment, the post-remission treatment generally begins two weeks after the complete remission is obtained for the first time, the chemotherapy scheme selects a plurality of new schemes besides the original scheme used for inducing the remission, wherein the new schemes comprise two large-dose strengthening schemes which are inserted in the new schemes, and the schemes are alternately and alternately carried out to carry out the strengthening and strengthening treatment.

Radiation therapy is often used as part of a pretreatment regimen in hematopoietic stem cell transplantation, but because the leukemia cells themselves are perfused in the human circulatory system, hematopoietic organs and infiltrated tissues, radiation therapy has certain limitations in leukemia therapy, typically used to locally irradiate significantly enlarged liver and spleen or lymph nodes to relieve symptoms, or used as a pretreatment prior to bone marrow transplantation to reduce rejection.

Bone Marrow Transplantation (BMT) is the treatment of choice currently prevalent in the treatment of leukemia, as bone marrow transplantation is a real method of treating leukemia. The superiority of bone marrow transplantation compared with common chemotherapy is fully reflected in acute leukemia, and the treatment can obviously improve the disease-free survival rate of patients with acute leukemia. According to massive case analysis of Fred Hutchinson cancer research center and IBMTR, the disease-free survival rate of AML can reach about 50% in 3 years after AML receives ALLo-BMT in first remission; while the 3-year disease-free survival rate of patients with concurrent chemotherapy is only 18-27%. BMT efficacy is affected by a number of factors, mainly BMT timing: the efficacy of the first remission of BMT is superior to the second remission period. Brotint et AL (1988) compared the first remission and second remission BMT results in AL patients and found that after the first remission BMT, the 5-year recurrence rate of the patients was 21% + -11% and the 5-year disease-free survival rate was 46% + -9%; the 5-year relapse rate and survival rate of patients after the second remission BMT were 56% and 22%, respectively. Similar results were obtained for the IBMTR and Seattle data. Therefore, patients with acute leukemia are preferably fed BMT in the first complete remission. The nature of the disease itself: the relationship between BMT efficacy and typing is not clear, and AML efficacy is generally considered superior to ALL for ALL patients. Age and general condition of the patient: since the older the age, the poorer the organ function, and the greater the possibility of various complications, particularly GVHD, occurring after BMT, it is prudent to perform allogeneic bone marrow transplantation in patients over 45 years old, and generally not to perform allogeneic bone marrow transplantation over 50 years old.

In recent years, targeted therapy of leukemia cells has become a development trend of leukemia therapy, and targeted killing of leukemia cells by using monoclonal antibodies, cytokines or genes and the like has a good application prospect in clinic and can become another cure means of leukemia.

In the patent field, the application of the compound in the field of treating leukemia is also wide. For example, CN102961374B discloses an application of a compound shown in formula I in preparation of a STAT3 inhibitor and a STAT3 inhibitor, the compound shown in formula I can obviously inhibit proliferation and survival of various tumor cells such as acute and chronic leukemia, multiple myeloma, lymphoma, lung cancer, prostate cancer, cervical cancer and the like, inhibit a STAT3 signal channel of the tumor cells, activate relevant factors for inducing apoptosis of the tumor cells, thereby inducing apoptosis of the tumor cells and achieving the effect of treating tumor diseases.

CN103751172B discloses the application of dixanthone compounds in the preparation of anti-leukemia drugs, and also includes a method for extracting 5 dixanthone compounds from hypericum japonicum medicinal materials. Leukemia cell activity experiments are carried out on the 5 natural dixanthone compounds, and results show that the 5 dixanthone compounds have inhibitory activity on leukemia cells K562, HL-60 and THP-1, and have better inhibitory activity on K562 cells. The 5 dixanthone compounds exert antitumor activity through BCL2 protein family, and according to the result of a leukemia solid tumor nude mouse model, the growth of tumors can be inhibited, and the life cycle of the tumor model can be prolonged.

CN100441222C discloses the application of compound PS-341 in the preparation of medicine for treating M2 type acute saccharic leukemia with t (8; 21) chromosome translocation. Solves the problems that most patients can obtain remission, but relapse quickly and gradually generate drug resistance to cause treatment failure and the drugs have large toxic and side effects because the existing AML M2 treatment mainly treats the chemotherapy of large dose of cytarabine combined with daunorubicin or desmethoxyrubicin.

In recent years, there have been studies showing that low concentrations of VEGF in normal humans are mainly associated with angiogenesis, and that malignant hematological diseases also have angiogenesis. Under the condition that VEGF in tumor cells is over-expressed, the concentration of VEGF in local tumor tissues is abnormally increased, the cardiovascular production is further promoted, nutrients are increased for the tumor cells, the growth and proliferation of the tumor cells are further promoted, and the method is also greatly related to the invasion and metastasis of the tumor cells. By comparing the serum VEGF expression level before the leukemia patient is treated with the serum VEGF expression level of a reference group, the VEGF expression level in the serum of the leukemia patient is far higher than that of a healthy population, and the VEGF expression level in the serum of the leukemia patient after the leukemia patient is subjected to standardized treatment is far lower than that before the leukemia patient is treated. VEGF has the main biological function of increasing vascular permeability, is a main induction factor for promoting cardiovascular generation, can stimulate endothelial cells to cause hyperproliferation of endothelial cells so as to promote neoangiogenesis, and deposits a large amount of fibrinogen in an extravascular matrix under the condition of increasing vascular permeability, so that nutrients are further provided for vascular production and tumor cell growth, and necessary conditions are provided for further invasion and metastasis of tumors. Therefore, the VEGF inhibitor has better application value in treating leukemia patients by using the VEGF inhibitor.

However, in these applications, the toxic effect of the compound is strong, and the compound is also lovely and lovely killed to human body while treating leukemia, so the inventor improves on the basis of the above, and provides a novel pharmaceutical composition for treating leukemia, which can reduce the toxicity of the compound and improve the inhibition effect.

Disclosure of Invention

There is still room for improvement in therapeutic effects of the drugs studied earlier by the inventors.

The invention aims to provide a compound and preparation and application thereof. The compound provided by the invention has a structure shown in formula 1, can effectively inhibit the growth of K562 leukemia cells, and has a good application prospect.

In another aspect of the present invention, there is provided a polypeptide capable of increasing the permeability of leukemia cell membrane, such as SEQ id no: 1 is shown. The polypeptide can obviously improve the permeability of K562 leukocyte cell membranes, improve cell leakage and inhibit cell growth.

Permeation peptide SEQ ID NO: 1:

in another aspect of the present invention, there is provided a composition comprising SEQ ID NO: 1 in combination with a compound of formula 1, a synergistically enhanced cell killing effect is achieved.

The invention also provides an antitumor drug composition, which is a common preparation in pharmacy prepared by taking the compound, the polypeptide and the pharmaceutically acceptable salt thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

The compounds and polypeptides of the invention may be formulated for administration either alone or in combination with one or more acceptable carriers. Such as solvents, diluents, and the like. Can be administered in oral dosage forms, such as tablet, capsule, dispersible powder, granule, etc.; can also be administered by injection, such as lyophilized powder for injection. The various dosage forms of the pharmaceutical compositions of the present invention may be prepared according to methods well known in the pharmaceutical art. These pharmaceutical preparations may contain, in combination with a carrier, for example Weight active ingredient, more usually about

Active ingredient in between. The dosage of the compounds and polypeptides of the present invention may be varied beyond this range depending on the severity of the disease or the dosage form.

The leukemia refers to acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute nonlymphocytic leukemia, chronic leukemia, plasma cell leukemia, chronic myelogenous leukemia, eosinophilic leukemia, basophilic leukemia, megakaryocytic leukemia, undifferentiated acute leukemia or histiophilic leukemia, and low-proliferative leukemia type drug-resistant leukemia.

Advantageous effects

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

the invention discloses the synergistic effect of the compound and the polypeptide for the first time, improves the membrane permeability and the cell killing effect of leukemia cells, has low toxicity to normal cells, can effectively inhibit the cell proliferation of the leukemia cells and induce the apoptosis of tumor cells, and has better application prospect.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of the drawings:

FIG. 1: cell culture time versus cell density.

Detailed Description