阅读说明：本技术 一种治疗aml的药物及应用 (Medicine for treating AML and application thereof ) 是由 曾辉 王惠雯 展会恩 姜欣雅 于 2020-07-30 设计创作，主要内容包括：本发明公开了一种治疗AML的药物,所述药物为AP-1抑制剂T5224,所述药物AP-1抑制剂T5224在制备抗AML药物中的应用；AP-1抑制剂T5224在AML细胞株中能抑制细胞的增殖和促进其凋亡,且不对正常细胞株的增殖造成明显的影响；T5224联合阿糖胞苷作用于AML细胞株,对AML细胞增殖的抑制较单用阿糖胞苷明显增强；T5224能增强AML细胞对化疗药物阿糖胞苷的敏感性,能促进阿糖胞苷对AML细胞的杀伤作用。(The invention discloses a medicine for treating AML, which is an AP-1 inhibitor T5224, and the application of the AP-1 inhibitor T5224 in preparing an anti-AML medicine; the AP-1 inhibitor T5224 can inhibit the proliferation of cells and promote the apoptosis of the cells in an AML cell strain, and does not cause obvious influence on the proliferation of a normal cell strain; the T5224 combined with cytarabine acts on AML cell strains, and the inhibition on AML cell proliferation is obviously enhanced compared with the inhibition on AML cell proliferation by singly using cytarabine; t5224 can enhance the sensitivity of AML cells to cytarabine, a chemotherapeutic drug, and promote the killing effect of cytarabine on AML cells.)

1. A medicament for treating AML, which is the AP-1 inhibitor T5224, wherein T5224 has the formula:

2. the medicament of claim 1, further comprising at least cytarabine.

3. Use of the drug AP-1 inhibitor T5224 according to claim 1 for the preparation of an anti-AML drug.

4. The use as claimed in claim 3, wherein the medicament comprises T5224 as the active ingredient, together with one or more pharmaceutically acceptable excipients selected from diluents, excipients, fillers, binders, wetting agents, absorption enhancers, surfactants, lubricants, stabilizers, flavoring agents, sweeteners and pigments, which are conventional in the pharmaceutical arts.

5. The use according to claim 4, wherein the medicament is a sensitizer for increasing the sensitivity of AML cells to chemotherapeutic drugs, such as cytarabine.

6. The use of claim 4, wherein the medicament is a pharmaceutical composition against AML comprising a pharmaceutically effective amount of T5224 and a pharmaceutically effective amount of cytarabine and a pharmaceutically acceptable carrier.

7. The use of any one of claims 4 to 6, wherein the medicament is formulated into any one of pharmaceutically acceptable dosage forms, including tablets, capsules, granules, oral liquids, sustained release preparations, nano preparations, injections.

Technical Field

The invention relates to the technical field of antitumor drugs, and particularly relates to a drug for treating AML and application thereof.

Background

Acute Myeloid Leukemia (AML) is a group of highly heterogeneous hematological malignancies caused by clonal proliferation of immature myeloid progenitor cells, and the standard treatment is induction of remission followed by consolidation chemotherapy or hematopoietic stem cell transplantation. Although as early as the 70's of the 20 th century, the combined use of the induction chemotherapy drugs daunorubicin and cytarabine could achieve Complete Remission (CR) in a large number of AML patients; however, in the last 40 years, treatment of AML has progressed slowly, with the exception of Acute Promyelocytic Leukemia (APL), and patient prognosis has remained poor. Therefore, new, effective therapeutic approaches are crucial for improving the prognosis of AML.

Human activin 1 (AP-1) is a homodimer or heterodimer formed by protein families of Jun (C-Jun, Jun-B, Jun-D), Fos (C-Fos, Fos-B, Fra-1, Fra-2), ATF (ATF2, ATF3, LRF1, B-ATF, JDP1, JDP2) and MAF (C-Maf, MafB, MafA, Maf) polygenes. AP-1 is an important transcription factor, participates in gene transcription of various growth factors and cytokines in cells, plays an important role in biological processes such as cell proliferation, apoptosis, differentiation, survival, migration, transformation and the like, and is increased in expression of various solid tumors and blood system tumors. Many studies in the early days have been devoted to the detection of AP-1 activity in tumor cells, but the results showed that its activity did not affect tumor cell survival. Therefore, recent studies have focused on the expression and activity of members of the JUN and Fos families in tumors. Among them, Fra-1 and c-Fos in Fos family are the most widely studied functions in tumors. Previous studies have shown that in hematological tumors, the expression levels of c-Fos, Jun and AP-1 are elevated in AML. Compared with the extensive research data of Fra-1 and c-Fos, FosB, Fra-2, FosB2 and delta FosB2 have been studied in tumors, and the expression and biological effect of FosB in AML has not been clarified. Importantly, FosB, as a proto-oncogene, can increase the invasive potential of breast cancer cells and promote the progression of pancreatic cancer. In pancreatic cancer, miR-144-3p targets proto-oncogene FosB, inhibiting proliferation, metastasis and invasion of pancreatic malignant tumor cells. T5224 is a specific non-peptide small molecule AP-1 inhibitor, which can inhibit the binding of the heterodimer AP-1 formed by Fos and Jun protein and the binding site of the promoter region AP-1, thereby inhibiting the activation of the AP-1 signaling pathway, but the effect in acute myelogenous leukemia is not reported yet.

Disclosure of Invention

The invention discovers that FosB in an AP-1 signaling pathway is remarkably improved in the refractory and recurrent groups of AML by detecting bone marrow samples of patients with acute myelogenous leukemia. The invention thus envisages: whether the AP-1 signaling pathway regulates the proliferation of AML can affect the sensitivity of AML cells to chemotherapeutic drugs. Aiming at the assumption, the invention takes acute myeloid leukemia cell strains and clinical samples as research objects to prove the assumption through experiments, and then, aiming at the proving fact, the invention takes the acute myeloid leukemia cell strains and clinical samples as research objects to discuss the effect of FosB in acute myeloid leukemia cells and the influence of FosB on the sensitivity of chemotherapeutic drug cytosine arabinoside (Ara-C), and verifies that AP-1 inhibitor T5224 can inhibit the proliferation of cells and promote the apoptosis of the cells in the acute myeloid leukemia cell strains under the condition of not obviously influencing the proliferation of normal cell strains, and can enhance the sensitivity of AML cell strains to Ara-C.

The invention aims to solve the problem of providing a new application of T5224, namely a new application in pharmacy. The invention aims to provide application of T5224 in preparing medicines for resisting acute myeloid leukemia and chemotherapy sensitization.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a medicament for treating AML which is the AP-1 inhibitor T5224, said T5224 having the formula:

preferably, the medicament further comprises at least cytarabine.

Preferably, the application of the medicine AP-1 inhibitor T5224 in preparing anti-AML medicines.

Preferably, the medicine takes T5224 as an active ingredient, and is added with one or more pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise diluents, excipients, fillers, adhesives, wetting agents, absorption promoters, surfactants, lubricants, stabilizers, flavoring agents, sweetening agents and pigments which are conventional in the pharmaceutical field.

Preferably, the drug is a sensitizer that increases the sensitivity of AML cells to chemotherapeutic drugs, such as cytarabine.

Preferably, the medicament is a pharmaceutical composition for treating AML, and the composition contains a pharmaceutically effective amount of T5224, a pharmaceutically effective amount of cytarabine and a pharmaceutically acceptable carrier.

Preferably, the medicine is prepared into any pharmaceutically acceptable dosage form, and the dosage form comprises tablets, capsules, granules, oral liquid, sustained release preparations, nano preparations and injections.

Compared with the prior art, the invention has the beneficial effects that:

1. the invention detects the cell killing effect of T5224 on cell strains, and finds that T5224 does not cause obvious influence on the proliferation of human umbilical vein endothelial cells;

2. t5224 can inhibit cell proliferation and promote apoptosis in acute myelogenous leukemia cell strain;

3. the T5224 combined with cytarabine acts on AML cell strains, and the inhibition on AML cell proliferation is obviously enhanced compared with the inhibition on AML cell proliferation by singly using cytarabine; t5224 can promote the killing effect of cytarabine on AML cells, and enhance the sensitivity of AML cells to chemotherapeutic drug cytarabine;

4. the invention provides a new drug for treating acute myeloid leukemia, T5224, which has no toxic or side effect on human body, and can be used together with chemotherapeutic drug cytarabine to promote the killing effect of cytarabine on AML cells, reduce the dose of cytarabine and reduce the toxic or side effect of chemotherapeutic drug on human body.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a graph of FosB expression in AML patients;

FIG. 2 is a graph showing the expression of FosB in normal cell lines and AML cell lines;

FIG. 3 is a graph showing the results of the proliferation of the stem cells of human umbilical vein endothelial cell line and AML cell line;

FIG. 4 is a graph showing the results of apoptosis of AML cells treated with different concentrations of T5224;

FIG. 5 is a graph showing the results of T5224 in combination with cytarabine on the proliferation of AML cells.

Detailed Description

The embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein the description is for illustrative purposes only and is not intended to limit the scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

A medicament for treating AML which is the AP-1 inhibitor T5224, said T5224 having the formula:

preferably, the medicament further comprises at least cytarabine.

Preferably, the application of the medicine AP-1 inhibitor T5224 in preparing anti-AML medicines.

Preferably, the medicine takes T5224 as an active ingredient, and is added with one or more pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise diluents, excipients, fillers, adhesives, wetting agents, absorption promoters, surfactants, lubricants, stabilizers, flavoring agents, sweetening agents and pigments which are conventional in the pharmaceutical field.

Preferably, the drug is a sensitizer that increases the sensitivity of AML cells to chemotherapeutic drugs, such as cytarabine.

Preferably, the medicament is a pharmaceutical composition for treating AML, and the composition contains a pharmaceutically effective amount of T5224, a pharmaceutically effective amount of cytarabine and a pharmaceutically acceptable carrier.

Preferably, the medicine is prepared into any pharmaceutically acceptable dosage form, and the dosage form comprises tablets, capsules, granules, oral liquid, sustained release preparations, nano preparations and injections.