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    Home > Medical News > Medical World News > New tumor target METTL3, potential first-in-class leukemia new drug appears

    New tumor target METTL3, potential first-in-class leukemia new drug appears

    • Last Update: 2021-05-10
    • Source: Internet
    • Author: User
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    Text | Bailu

    Scientists have taken another landmark step in the development of new drugs for acute myeloid leukemia (AML).

    On April 26, researchers from the University of Cambridge published a study in the journal Nature, reporting a new treatment for AML.
    This method uses methyltransferase like protein (METTL)3 as the target, which plays a key role in the process of converting DNA into protein, and develops a small drug molecule STM2457.
    Studies have shown that STM2457 can effectively destroy the proliferation and expansion of leukemia cells in the AML mouse model, and significantly extend the lifespan of mice.

    Source: Nature

    Source: Nature

    Professor Tony Kouzarides, who led the research, said: “Protein plays a vital role in our body functions.
    It is produced through a process that involves the use of enzymes to convert DNA into RNA.
    Sometimes this process can go wrong and give humans Health brings potentially devastating consequences.
    However, so far, no one has used this important process as a means of fighting cancer.
    This is the beginning of a new era of cancer treatment.
    "

    METTL3 target global research status (data source: NextPharma)

    METTL3 target global research status (data source: NextPharma)

    There are more than 170 modifications in RNA, of which N6-methyladenine (m6A) methylation is one of the most common epigenetic modifications on RNA molecules.
    Disorders in the regulation of m6A methylation modification may affect the process of mRNA processing, degradation and translation, leading to the activation of oncogenes and the inactivation of tumor suppressor genes, and the occurrence, development and resistance of malignant tumors (including hematomas and solid tumors).
    Occurrence is closely related.
    Among the enzymes involved in m6A methylation modification, METTL3 is the catalytic core.

    Schematic diagram of the domain of METTL3 (Source: Journal of Hematology & Oncology)

    Schematic diagram of the domain of METTL3 (Source: Journal of Hematology & Oncology)

    In fact, as early as 2017, a team led by Professor Kouzardides published a study in the journal Nature, pointing out that the METTL3 enzyme plays a key role in the development and maintenance of AML, and identified this enzyme as a potential therapeutic target for AML.

    Source: Nature

    Source: Nature

    Now, Professor Kouzardides and his colleagues have discovered a drug-like small molecule STM2457 that can inhibit METL3.
    STM2457 is highly specific to METTL3 and has no inhibitory effect on other RNA methyltransferases.
    Studies have shown that in tissue cultures of AML patients and AML mouse models, this small molecule can block the cancerous effects caused by overexpression of METTL3.

    Source: Nature

    Source: Nature

    Specifically, in order to study the anti-leukemia potential of STM2457, the researchers tested the molecule on cell lines from AML patients and found that it significantly reduced the growth and proliferation of these cells in a concentration-dependent manner (Figure a below).
    In addition, treatment with STM2457 induced apoptosis in AML patient cells and cells in mouse AML models, but did not induce apoptosis in normal non-leukemic hematopoietic cells (Figure b, c below)

    Source: Nature

    Source: Nature

    After obtaining positive evidence in in vitro experiments, the researchers transplanted cells from AML patients into immunocompromised mice to establish a disease model and treated the mice with STM2457.
    They found that STM2457 disrupted the proliferation and expansion of transplanted cells, and significantly prolonged the lifespan of the mice (Figure ad below).
    The reduction of human CD45+ cells in the bone marrow and spleen of mice after treatment also confirmed the anti-leukemia effect (Figure e below), and there are no toxic side effects, including no effect on body weight.

    In vivo studies have shown that STM2457 can prevent the expansion of AML and reduce key leukemia stem cells (Source: Nature)

    In vivo studies have shown that STM2457 can prevent the expansion of AML and reduce key leukemia stem cells (Source: Nature)

    Collectively, these results reveal that METL3 inhibition can be used as a potential therapeutic strategy for anti-AML, and provide a proof of concept for targeting RNA-modifying enzymes as a promising new approach to anti-cancer therapy.

    "This is a brand-new area of ​​cancer research.
    STM2457 is also the first METL3 targeted drug to prove bioavailability in tumor models.
    It has shown excellent activity in killing leukemia cells and prolonging the lifespan of mice.
    We hope that Start clinical trials in 2022 and test subsequent optimized molecules on patients.
    We believe that METL3 targeted therapy can be used to treat a variety of cancers and is expected to become a new weapon against tumors.
    ” Dr.
    Konstantinos Tzelepis, who co-led the research, added .

    Reference materials:

    Reference materials:

    1# Eliza Yankova et al.
    Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
    Nature.
    2021

    1# Eliza Yankova et al.
    Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia.
    Nature.
    2021

    2# Isaia Barbieri et al.
    Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.
    Nature.
    2017

    2# Isaia Barbieri et al.
    Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.
    Nature.
    2017

    3# Scientists develop new class of cancer drug with potential to treat leukaemia (Source: University of Cambridge official website)

    3# Scientists develop new class of cancer drug with potential to treat leukaemia (Source: University of Cambridge official website)

    4# Chengwu Zeng et al.
    Roles of METTL3 in cancer: mechanisms and therapeutic targeting.
    Journal of Hematology & Oncology.
    2020

    4# Chengwu Zeng et al.
    Roles of METTL3 in cancer: mechanisms and therapeutic targeting.
    Journal of Hematology & Oncology.
    2020

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