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Application of Ponatinib in preparing drugs for treating fungal infections

A technology of fungal infection and ponatinib, applied in the direction of antifungal agents, pharmaceutical formulations, medical preparations containing active ingredients, etc., to achieve the effects of increasing accumulation, promoting killing activity, and good killing effect

Active Publication Date: 2019-12-31
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Ponatinib is an oral multi-target tyrosine kinase inhibitor (CAS No.: 943319-70-8) developed by Ariad Pharmaceuticals, which was approved for marketing in the United States in December 2012 , which was approved in the European Union through the centralized approval process in July 2013, for the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, but the application of this drug in fungal infection drugs has not been reported

Method used

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  • Application of Ponatinib in preparing drugs for treating fungal infections
  • Application of Ponatinib in preparing drugs for treating fungal infections
  • Application of Ponatinib in preparing drugs for treating fungal infections

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Inhibitory effect of ponatinib and fluconazole on the growth of Candida albicans cells and mycelia

[0033] Experimental process: In a 96-well plate, prepare doubly diluted fluconazole along the Y axis and doubly diluted ponatinib along the X axis, with a final volume of 100 μl per well, and then place the white rosary recovered from -80°C Bacterial suspension (OD 600 =0.02), then inoculated in a 96-well plate containing drugs (100 μl / well), incubated at 30°C, and detected OD with a microplate reader after 16 hours 600 . The FICI of a drug combination is determined from a single FIC value (FIC=[x] / MICx, where [x] is the minimum inhibitory concentration of the drug in combination, FICI=FIC ponatinib +FIC fluconazole ).

[0034]The minimum inhibitory concentration (Minimal Inhibitory Concentration, MIC) of fluconazole against Candida albicans was 1.63 μM, and the MIC of ponatinib against Candida albicans was 4 μM. Natinib increased the sensitivity of Candida albicans...

Embodiment 2

[0039] Inhibition of ponatinib and fluconazole against other fungi (Saccharomyces cerevisiae, Cryptococcus neoformans, Aspergillus fumigatus)

[0040] Experimental process: In a 96-well plate, prepare doubly diluted fluconazole or voriconazole along the Y axis and doubly diluted ponatinib along the X axis, with a final volume of 100 μl per well, and then place the recovered from -80°C Bacterial suspension (OD 600 or OD 530 =0.02), then inoculated in a 96-well plate containing drugs (100 μl / well), incubated at 30°C, and detected OD with a microplate reader after 16 hours 600 or OD 530 . The FICI of a drug combination is determined from a single FIC value (FIC=[x] / MICx, where [x] is the minimum inhibitory concentration of the drug in combination, FICI=FIC ponatinib +FIC antifungal ).

[0041] The MIC of fluconazole on Saccharomyces cerevisiae was 52.29 μM, and when Ponatinib was used alone, the inhibitory effect on Saccharomyces cerevisiae was not significant, but when flu...

Embodiment 3

[0051] Bacteriostatic effect of ponatinib and fluconazole on clinical fluconazole-resistant strains

[0052] Experimental process: In a 96-well plate, prepare doubly diluted fluconazole along the X axis, with a final volume of 100 μl per well, and then make a bacterial suspension (OD 600 =0.02), then inoculated in a 96-well plate containing drugs (100 μl / well), incubated at 30°C, and detected OD with a microplate reader after 16 hours 600 .

[0053] The MICs of fluconazole against FLC-resistant Candida albicans CCC49 and CCC80 were 104.58 μM and 52.29 μM, respectively. Fluconazole was applied to clinical fluconazole-resistant strains with a certain concentration gradient, and incubated at 30°C for 16 hours. Detect OD 600 , and finally make a histogram, such as figure 2 shown;

[0054] Experimental process: In a 96-well plate, prepare doubly diluted fluconazole along the Y-axis and doubly diluted ponatinib along the X-axis, with a final volume of 100 μl per well, and then ...

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Abstract

The invention belongs to the field of pharmaceutical preparation, and in particular relates to application of Ponatinib in preparing drugs for treating fungal infections. Ponatinib has a therapeutic effect on fungal infections, especially when used in combination with fluonazole, not only has a good fungistatic effect, but also achieves a fungicidal effect against fungal infections; and furthermore, Ponatinib has a broad-spectrum antifungal effect, and has good killing effects on fluconazole-resistant Candida albicans strains, Cryptococcus neoformans and Saccharomyces cerevisiae. According tothe present invention, a gene PDR5 and a gene PMA1 are found to be drug targets of Ponatinib for antifungal infection effect, and a new development direction and action mechanism for the treatment offungal infections and research and development of therapeutic drugs are provided.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and particularly relates to the application of ponatinib in the preparation of medicines for treating fungal infections. Background technique [0002] Fungal infection is a serious threat to human health. Every year, billions of people are infected worldwide, resulting in more than 1.5 million deaths. At present, there are roughly three categories of drugs clinically used for fungal infections: polyenes, azoles, and echinocandins. Polyenes, introduced 60 years ago, exert their bactericidal activity by binding to ergosterol on fungal cell membranes. Azole drugs were discovered 40 years ago and are currently the most widely used antifungal drugs. They inhibit ergosterol synthase (lanosterol 14α-demethylase), causing blockage of ergosterol synthesis and C-14 methyl The accumulation of sterols can achieve the purpose of inhibiting the growth of fungi. Echinocandins, which came out more than 10 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5025A61P31/10A61K31/4196A61K31/506
CPCA61K31/5025A61P31/10A61K31/4196A61K31/506A61K2300/00
Inventor 王慧刘宁宁
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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