Medicament target for treating acute promyelocytic leukemia and inhibitor thereof

A promyelocytic and leukemia technology, applied in the field of drug preparation for leukemia treatment, can solve problems such as ATRA drug resistance, and achieve the effects of good stability, good medicinal prospects and strong pharmacological effects

Inactive Publication Date: 2013-04-17
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although ATRA can induce clinical complete remission in most APL patients, almost all patients relapse shortly after complete remission if only ATRA is used as maintenance

Method used

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  • Medicament target for treating acute promyelocytic leukemia and inhibitor thereof
  • Medicament target for treating acute promyelocytic leukemia and inhibitor thereof
  • Medicament target for treating acute promyelocytic leukemia and inhibitor thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: Knockout of Prx I / II directly inhibits cell proliferation and induces differentiation of NB4 cells.

[0021] Our study found that after 6 days of infection of NB4 cells with Prx I / II reverse transcription knockout virus, NB4 cells were obviously elongated and adhered to the wall. The basal blue tetrazolium reduction test found that the positive cells increased significantly ( figure 1 A), further using flow cytometry to detect the cell surface differentiation antigen CD11b / c, it was found that knocking out Prx I / II significantly up-regulated its expression ( figure 1 B). These results suggest that knockdown of Prx I / II directly induces NB4 cell differentiation. Further studies showed that cell proliferation was significantly inhibited after knocking out Prx I / II ( figure 1 C), through flow cytometry analysis, it was found that after knocking out Prx I / II, the cells were arrested in G1 phase ( figure 1 D). The knockout effect of Prx I / II and the expressio...

Embodiment 2

[0022] Example 2: Knockout of Prx I / II directly induces the differentiation of all-trans retinoic acid-resistant acute promyelocytic leukemia cells.

[0023] All-trans retinoic acid-resistant acute promyelocytic leukemia cells (NB4-MR2 and NB4-LR2) were infected with Prx I / II reverse transcription knockout virus for 6 days, and Wright's Giemsa staining showed that the ratio of nuclei to plasma was significantly reduced , presenting a myeloid differentiated phenotype ( figure 2 A). The nitro blue tetrazolium reduction test showed that the positive cells increased significantly ( figure 2 B). The knockout effect of Prx I / II and the expression of differentiation-related gene C / EBPβ were detected by Western blotting ( figure 2 C). The results of Examples 1 and 2 show that Prx I / II can be used as a new potential target for induction and differentiation therapy of acute promyelocytic leukemia and can be applied to the screening of anti-leukemia drugs.

Embodiment 3

[0024] Example 3: Adenoletin and its derivatives are novel Prx I / II inhibitors.

[0025] We established a Prx I / II enzyme activity detection platform in vitro, including in vitro recombinant Prx I / II, Trx / TrxR, the substrate is NADPH, and the reaction initiator is H 2 o 2 , Prx I / II can restore H 2 o 2 , and the oxidized Prx I / II is reduced by NADPH by Trx / TrxR. The activity of Prx I / II was reflected by detecting the content of NADPH. Use this platform to screen Prx I / II inhibitors in order to discover new lead compounds for the treatment of leukemia. We screened and found that adenolin ( image 3 A, compound No. 1) can inhibit the activity of Prx I in a dose-dependent manner ( image 3 B). This suggests that adenflowerin may be a Prx I / II inhibitor. In order to further elucidate the structure-activity relationship of adenoflavin in inhibiting the activity of Prx I / II, we obtained four derivatives through chemical modification: Compound No. 4 with C(16)-C(17) double bo...

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Abstract

The invention provides an application of Prx I/II in screening of medicaments for treating leukemia, wherein the Prx I/II is used as a medicament target to screen medicaments which inhibits PRX I/II enzyme activity and thus has a differentiation effect on leukemia cells. According to the invention, screened adenanthin and derivatives thereof are used for realizing the differentiation effect for acute promyelocytic leukemia, thereby showing significant effects for treating all-trans retinoic acid sensitive and all-trans retinoic acid resistant leukemia. The adenanthin is safe, low in toxicity and strong in pharmacological effect, and indicates good medicinal prospects. The adenanthin active substance provided by the invention has characteristics of easy absorption, good stability, etc., and is relatively suitable for developing as novel medicaments, foods, health products or dietary additives.

Description

technical field [0001] The invention relates to the preparation of medicines for treating leukemia, and more specifically, relates to a medicine target for treating acute promyelocytic leukemia and an inhibitor thereof. Background technique [0002] Leukemia is a malignant tumor of the hematopoietic system that seriously endangers human life and health. Among them, acute myeloid leukemia (AML) has received more attention due to its rapid onset and high mortality. On the other hand, due to the convenience of obtaining leukemia materials and the ease of observing the curative effect, the research on the pathogenesis and treatment of AML has made remarkable progress in the past ten years. It is believed that future breakthroughs in cancer therapy may first come from research on leukemia. AML is characterized by the blockage of myeloid precursor cell differentiation at different stages, and is divided into M1-M7 subtypes according to the diagnostic criteria of the American-Bri...

Claims

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Application Information

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IPC IPC(8): C12Q1/26A61K31/4188A61K31/22A61P35/02
Inventor 陈国强孙汉董吴英理刘传绪阴倩倩普建新肖伟烈
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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