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Application of RNA helicase DHX33 inhibitor in preparation of medicine for treatment of leukemia

A technology of DHX33 and leukemia, applied in the field of biomedicine, can solve the problems of poor targeting of therapeutic drugs, no obvious improvement in the treatment of acute leukemia, and inability to fully achieve the expected therapeutic effect, and achieve the inhibition of programmed cell apoptosis. Important medicine development value, efficacy in the treatment of leukemia

Active Publication Date: 2021-11-09
SHENZHEN KEYE HEALTH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In summary, the treatment of various acute leukemias has not improved significantly, and there are problems such as poor targeting of therapeutic drugs and inability to fully achieve the expected therapeutic effect.

Method used

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  • Application of RNA helicase DHX33 inhibitor in preparation of medicine for treatment of leukemia
  • Application of RNA helicase DHX33 inhibitor in preparation of medicine for treatment of leukemia
  • Application of RNA helicase DHX33 inhibitor in preparation of medicine for treatment of leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1D

[0124] Example 1 DHX33 protein inhibitors play an important role in lymphocytic leukemia, and the inhibition of DHX33 protein significantly inhibits the growth of lymphocytic leukemia cells

[0125] A variety of human leukemia model cell lines were cultured in vitro, including Jurkat T cell line, Raji cell line, Daudi cell line, K562 cell line and Nalm6 cell line, and cell activity experiments were performed in vitro. Jurkat cells, a suspension cell, are a model cell used to study human acute T-cell leukemia. Raji is a human B-lymphoma cell model, which is of B-cell origin. The Daudi cell line is a human Burkkit lymphoma cell, which carries Epstein-Barr virus, and is a typical B lymphoblastoid cell line, which is used for the study of the pathogenesis of leukemia. The K562 cell line is a human chronic myeloid leukemia cell line. The Nalm6 cell line is a human acute lymphoblastic leukemia cell line.

[0126] experiment as figure 1 As shown, compared with the DMSO control gr...

Embodiment 2D

[0131] Example 2 The programmed apoptosis induced by DHX33 inhibitor is the main cause of leukemia cell death

[0132] The B-cell lymphoma-2 gene is referred to as Bcl-2 (B-cell lymphoma-2), which is the B-cell lymphoma / leukemia-2 gene. The role of apoptosis, it is often highly expressed in leukemia cells. BCL2 gene was down-regulated in Jurkat T cells treated with DHX33 protein inhibitor A.

[0133] BMF (bcl-2-modifying factor) is a member of the Bcl-2 family with pro-apoptotic effects. Under normal physiological conditions, endogenous BMF is continuously anchored to the cytoskeleton in the cytoplasm, and it always senses the intracellular Once the injury stimulus acts on the cells, BMF transfers from the cytoplasm to the mitochondria, triggers the mitochondrial apoptotic pathway, and induces apoptosis. The Jurkat T cells treated with the DHX33 inhibitor compound A up-regulated the BMF gene, which promoted the apoptosis of leukemia cells.

[0134] As a member of Bcl-2 fami...

Embodiment 3

[0136] The highly active compound C obtained after optimization in Example 3 is more effective in inducing programmed apoptosis of cancer cells

[0137] Because compound A has a higher half-inhibitory concentration of cells, that is, the activity is relatively low, compound B was selected after molecular optimization of compound A (IC 50 =10-20nM) and compound C (IC 50 =0.15 μM) (see CN112661754A) to further analyze the apoptosis-inducing effect of DHX33 inhibitors on leukemia cells. Figure 9 Shows the half-inhibitory concentration analysis of Jurkat T cells treated with compounds B, C and D, and the results show that the inhibitor concentrations of these compounds in Jurkat T cells, i.e. IC 50 , between 0.025 and 0.18 μM, the activity of compound A is significantly improved.

[0138] First, on the basis of increasing the dose of compound C, the apoptosis index was analyzed. Cancer cells were treated with 0, 0.1, 0.25, 0.5, and 1 μM for 24 hours. After the cells were harve...

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Abstract

The invention discloses application of an RNA helicase DHX33 inhibitor in preparation of a medicine for treatment or adjuvant treatment of leukemia. According to the invention, the important effect of a DHX33 protein in leukemia development is determined, a provided small molecule compound has the effect of inhibiting the DHX33 helicase activity so as to promote leukemia cancer cell apoptosis mediated by a BCL-2 family protein regulated and controlled by the DHX33, and the small molecule compound can rapidly induce leukemia cell apoptosis, but is not lethal to normal blood cells, and thus has the important medical development value.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to the application of RNA helicase DHX33 inhibitors in the preparation of medicines for treating leukemia. Background technique [0002] Leukemia is a kind of malignant hematological tumor with abnormal proliferation of hematopoietic stem cells. In my country, the incidence of leukemia ranks sixth in the incidence of various tumor diseases, usually due to changes in important genes that regulate biological processes such as cell growth and apoptosis. And caused. According to the mechanism of leukemia pathogenesis, the source of cancerous cells and other characteristics, specific treatment can be carried out for different types of leukemia. Among leukemias, leukemias with ideal therapeutic effect include hairy cell leukemia (HCL), acute promyelocytic leukemia (APL), core binding factor leukemia (CBF) and chronic myeloid leukemia (CML). In recent years, due to the development o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184A61K31/437A61P35/02C07D405/14C07D471/04C07D409/14
CPCA61K31/4184A61K31/437A61P35/02C07D405/14C07D471/04C07D409/14
Inventor 张严冬聂光丽李相鲁
Owner SHENZHEN KEYE HEALTH CO LTD
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