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    Home > Active Ingredient News > Drugs Articles > Quinazoline drug development for bladder cancer: multi-mechanism resistance to drug resistance

    Quinazoline drug development for bladder cancer: multi-mechanism resistance to drug resistance

    • Last Update: 2021-06-30
    • Source: Internet
    • Author: User
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    Bladder cancer is one of the major public health problems in the world.
    Its incidence ranks 9th among global malignant tumors, and 2nd among urinary system tumors, with 400-500,000 new cases each year
    .


    More than 70% of new bladder cancers are non-muscular invasive bladder cancer (NMIBC), and the mortality rate is relatively low


    Recently, based on the application of quinazoline drug development and the important role of sorafenib and other diarylurea molecules in tumor treatment, researchers have developed a new class of quinazoline-arylurea bladder cancer drugs And found a powerful, multi-mechanism drug molecule 7j that resists drug resistance
    .

    Figure 1: Synthesis of quinazoline bladder cancer drugs

    As shown in the figure, the researchers first synthesized a series of quinazoline-arylurea drug molecules through the route shown in Figure 1
    .


    This route uses methyl anthranilate molecules as raw materials, through the formation of quinazoline ring, chlorination, nucleophilic substitution, and reaction with aryl isocyanate to form urea to obtain 7a-q, 8a-q multiple quinazoles Phloline-arylurea drug molecule


    Figure 2 Anti-proliferative activity experiment of tumor cells

    Subsequently, the researchers found through the anti-proliferative activity experiment of tumor cells that among the synthesized quinazoline derivatives, compound 7j has higher anti-proliferative activity, and it has many effects on BEL-7402, MGC-803, T24, HCV29, SI, etc.
    This tumor cell showed a low IC50 value, especially for the bladder cancer cell T24, its IC50=3.
    97μM
    .

    Figure 3 Study on the effect and mechanism of compound 7j in promoting apoptosis

    Next, the researchers confirmed that compound 7j is superior to sorafenib and gefitinib in its inhibitory activity on bladder cancer cell T24, and found that 7j has an excellent pro-apoptotic effect, and it is also superior to sorafenib in its pro-apoptotic effect.
    Rafenib and Gefitinib
    .


    In terms of mechanism, compound 7j can reduce the expression of caspases-8 and caspases-3, promote the expression of Bax and Bcl-x1, and reduce the expression of Bcl-2


           Figure 4 Study on the effect and mechanism of compound 7j in promoting iron death

           Interestingly, further studies have found that compound 7j can also produce anti-cancer effects by promoting iron death
    .


    As shown in Figure 4A, compound 7j can have a synergistic anticancer effect with the iron death promoter erastin, and the iron death inhibitor can reduce the anticancer effect of compound 7j


           Figure 5 Summary of anti-tumor mechanism of compound 7j

           In addition, the researchers also found through research that compound 7j can also promote tumor cell autophagy through the PI3K-Akt-mTOR-ULK1 pathway
    .


    The anti-tumor mechanism of compound 7j is summarized as shown in Figure 5.


           In general, the new research has developed a new class of quinazoline drug molecules, and through activity experiments have found the leading compound 7j for the treatment of bladder cancer , which can promote apoptosis, iron death, and autophagy.


           *The pictures in the text are from reference source 1

           references:

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