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Application of GNF-7 in preparation of FLT3 mutant inhibitor

A technology of 1.GNF-7 and 7.GNF-7, applied in the field of medicine, can solve problems such as recurrence and drug resistance, achieve good therapeutic effects, good application prospects, and overcome drug resistance mutations

Pending Publication Date: 2022-03-15
GUANGZHOU WOMEN AND CHILDRENS MEDICAL CENTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although FLT3 inhibitors such as sorafenib (sorafenib) and quizartinib (AC220) can produce better therapeutic responses in the clinical application of FLT3-ITD positive AML patients, most patients have a few months after treatment. Drug resistance is prone to appear within one year to lead to relapse; mutation sites such as D835 (D835F / H / V / Y), F691L are important causes of sorafenib and quizartinib drug resistance and relapse, and F691L is Drug-resistant mutations that are currently difficult to overcome are called "gatekeeper mutations"

Method used

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  • Application of GNF-7 in preparation of FLT3 mutant inhibitor
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  • Application of GNF-7 in preparation of FLT3 mutant inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0057] In this example, FLT3-ITD AML cells were used as the experimental object to detect the effect of GNF-7 on the proliferation of FLT3-ITD AML cells and the activation of FLT3 signaling pathway.

[0058] (1) GNF-7 can inhibit the proliferation of FLT3-ITD AML cells

[0059] Experimental method: U937, THP-1, MOLM-13, MV-4-11, BaF3-FLT3-ITD and BaF3-FLT3-ITD-F691L cells were planted in a 96-well plate at an appropriate cell density, and passed through the same concentration gradient (1.111, 0.370, 0.123, 0.041, 0.014, 0.005, 0.002μM) GNF-7 was treated for 48 hours and then Cell TilterGlo detection reagent was used to detect cell proliferation. 100 μl CellTiter-Glo reagent was added to each treatment well, and left at room temperature. Place and incubate for 30 minutes, mix well and transfer 50 μl into a 384-well plate to detect the corresponding fluorescence value in a microplate reader, and calculate the cell proliferation rate or cell viability according to the fluorescenc...

Embodiment 2

[0071] In this example, BaF3-FLT3-ITD+F691L cells and BaF3-FLT3-ITD cells were used as experimental objects to detect the effect of GNF-7 on FLT3-ITD+F691L (FLT3-ITD-F691L) mutation and FLT3-ITD mutation.

[0072] Experimental method: (1) BaF3-FLT3-ITD and BaF3-FLT3-ITD+F691L cells were treated with AC220 and GNF-7 at different concentrations (1.111, 0.370, 0.123, 0.041, 0.014, 0.005, 0.002μM) for 48 hours Afterwards, cell proliferation was detected with CellTilterGlo.

[0073] (2) Detect the apoptosis rate of BaF3-FLT3-ITD and BaF3-FLT3-ITD+F691L cells under the same concentration (0, 50nM, 100nM) of AC220 and GNF-7. The specific experimental steps include: collecting BaF3- Wash FLT3-ITD and BaF3-FLT3-ITD+F691L cells once with pre-cooled PBS, then centrifuge at 400g at 4°C for 5 minutes, discard the supernatant, resuspend the cells in 100μL 1×Binding Buffer, add 5μL AnnexinV APC , 5 μL of PI, mixed gently, and placed at room temperature for 15 minutes in the dark, then trans...

Embodiment 3

[0077] In this example, BaF3-FLT3-ITD+F691L transplanted mice were used as experimental subjects, and the effect of GNF-7 on the survival time of BaF3-FLT3-ITD+F691L transplanted mice was detected by animal experiments.

[0078] Experimental methods: (1) Construct a mouse animal model that induces leukemia, specifically including: transplanting BaF3-FLT3-ITD+F691L cells into BALB / c mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) A mouse animal model of induced leukemia was constructed.

[0079] (2) Divide the mouse animal model induced by leukaemia into three groups, namely con, 10mg / kg AC220 and 10mg / kg GNF-7 groups. After culturing the mouse animal model for 2 days, the mice were treated with con, 10mg / kg AC220 and 10mg / kg GNF-7 were treated, and the peripheral blood of the mice was collected 5 days later. After the peripheral blood was lysed with red blood cells, the cells were collected, and the leukemic cell load was detected by flow c...

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Abstract

The invention discloses an application of GNF-7 in preparation of an FLT3 mutant inhibitor. The GNF-7 provided by the invention can be in targeted combination with FLT3-ITD and F691L, overcomes drug-resistant mutation of F691L, achieves a better treatment effect on acute myelogenous leukemia compared with quinatinib AC220, and has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to the application of GNF-7 in the preparation of FLT3 mutant inhibitors. Background technique [0002] Acute myeloid leukemia (AML) is a hematologic malignancy in which hematopoietic progenitors acquire genetic mutations and / or chromosomal rearrangements that drive the expansion of immature myeloid cell populations. AML is the most common acute leukemia in adults with high morbidity and mortality. Currently, intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the main treatments. However, the prognosis of AML is very poor, and the cure rate is only 30-40%. [0003] FLT3 is one of the most frequently mutated genes in AML, with about 30% of patients found to contain internal tandem duplication (ITD) mutations, and 5%–10% of patients with point mutations in the tyrosine kinase domain, both of which Both forms can activate FLT3 receptor signa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/02
CPCA61K31/519A61P35/02
Inventor 肖新华单惠庄江华王培鸿
Owner GUANGZHOU WOMEN AND CHILDRENS MEDICAL CENTER
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