Nature | First report of METL3 inhibitors with active in vivo, which can significantly inhibit the process of acute myeloid leukemia

Written by Xiaoyou | Xi As the most abundant methylation modification in mRNA, m6A (N6-methyladenosine) has received widespread attention and led the rapid development of RNA epigenetics.

RNA m6A modification plays an important role in mRNA fate determination, which can affect RNA stability, alternative splicing, nucleation and translation efficiency.

Studies based on m6A methylases (METTL3, METL14, etc.
) and demethylases (FTO and ALKBH5) not only reveal the important role of m6A in diseases, especially cancer, but also provide new treatments for diseases target.

Professor Chen Jianjun of the Beckman Institute in the City of Hope in the United States determined the carcinogenic function of m6A demethylase FTO in acute myeloid leukemia in 2016 (see BioArt report: University of Chicago Chen Jianjun, He Chuan Group Cancer Cell reported obesity genes FTO overexpression leads to leukemiaBioArt focus), and in 2019, cooperated with Yang Caiguang Research Institute of Shanghai Institute of Materia Medica, Chinese Academy of Sciences to screen FTO small molecule inhibitors, FB23 and FB23-2 (see BioArt report: Expert Comments Cancer Cell | Yang Caiguang/ The Chen Jianjun/Qian Zhijian team developed FTO inhibitors for anti-leukemia treatment).

FB23-2 can inhibit the development of leukemia, but has a milder killing effect on cancer cells.
For this reason, Professor Chen Jianjun further screened more efficient FTO inhibitors.Fortunately, in 2020, Professor Chen Jianjun’s team discovered that two small molecule compounds CS1 (Bisantrene) and CS2 (Brequinara) can be used as more potent FTO inhibitors, and the use of this inhibitor can not only reduce the number of leukemia stem cells, but also Significantly inhibiting the immune escape of leukemia cells has important clinical significance (see BioArt report: Cancer Cell | Chen Jianjun's team develops new FTO inhibitors and reveals the role and mechanism of FTO in leukemia stem cells and immune escape).

In addition, in 2019, the Beijing Institute of Biological Sciences (NIBS) Scalper Laboratory, Zhang Erquan Laboratory and Beijing Institute of Genomics (BIG) Yang Yungui Laboratory of the Chinese Academy of Sciences jointly discovered that the old drug entacapone can be used as a potential FTO inhibitor and is expected to be used to treat obesity Clinical treatment of metabolic syndrome such as disease, diabetes, etc.
(For details, see BioArt report: New use of old drugsHuang Niu/Zhang Erquan/Yang Yungui found that FTO inhibitors may treat metabolic syndrome in cooperation).

Compared with the intensive research on FTO inhibitors, the development of small-molecule drugs for the methylase complexes METL3 and METL14, which also have important functions in m6A regulation, is much slower.

In 2019 and 2020, Mati Karelson from Estonia and Amedeo Caflisch from Denmark respectively identified agonists and inhibitors of METTL3 [1,2], but unfortunately there is a lack of research on the activity of these small molecule compounds in cells.

Therefore, no m6A methylase drugs with in vivo activity have been reported.

On April 26, 2021, Tony Kouzarides, Konstantinos Tzelepis and Oliver Rausch from the University of Cambridge and Babraham Research Campus (Babraham Research Campus) published the study "Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia" in Nature, The METL3 inhibitor STM2457 with in vivo activity was identified for the first time, and it was proved that STM2457 can significantly inhibit the process of acute myeloid leukemia.

 In order to screen for effective METL3 inhibitors, the researchers conducted high-throughput screening of 250,000 drug-like compounds and found two non-SAM (S-adenosyl methionine) related The chemical is a potential METL3 inhibitor.

Among them, the IC50 of STM2457 is 51.
7μM, which is better than STM2120 (IC50=64.
5μM).

Therefore, researchers mainly study the inhibitory effect of STM2457 on METTL3.

Structure analysis and enzyme activity experiments found that STM2457 can directly bind to the SAM binding site of METL3 (Figure 1), thereby inhibiting the activity of the methyltransferase of METL3.

Moreover, STM2457 does not affect the functions of other methylases.

Therefore, STM2457 is a specific inhibitor of METTL3.

 Figure 1.
STM2457 combined with METL3.
Previous studies have shown that METL3 functions as an oncogene in acute myeloid leukemia [3,4].
To this end, the researchers explored the killing effect of STM2457 on leukemia cells.

Cytological experiments show that adding STM2457 to the culture medium can significantly inhibit the proliferation of leukemia cells and promote cell differentiation and apoptosis.

It has no effect on normal hematopoietic stem cells.

In the primary cancer cells of acute myeloid leukemia, the researchers also obtained similar results.

Importantly, by comparing the changes in m6A and gene expression after STM2457 treatment and knockdown of METL3, the researchers found that STM2457 can significantly reduce the m6A level of the METL3 target gene and inhibit the translation of the gene (Figure 2).

This shows that the killing effect of STM2457 on cancer cells is dependent on the methyltransferase activity of METTL3.

 Figure 2.
STM2457 inhibits translation by regulating m6A.
Finally, in a mouse model, the researchers found that STM2457 treatment can significantly prolong the survival time of tumor-bearing mice (Figure 3) without affecting hematopoietic stem/progenitor cells, peripheral blood cells and small cells.
The weight of the mouse indicates that STM2457 specifically kills leukemia cancer cells, but has less side effects on normal cells.

Figure 3.
STM2457 treatment prolongs the survival time of leukemia mice.
In general, the study screened and identified the specific inhibitor STM2457 of METL3, and found that STM2457 regulates m6A levels in a METL3 enzyme activity-dependent manner and affects m6A-positive genes.
Translation, thereby inhibiting the process of acute myeloid leukemia.

Importantly, STM2457 does not affect the function of normal hematopoietic stem cells and other normal cells, suggesting that STM2457 can be used as a targeted drug for leukemia cancer cells and has important clinical significance.

 Original link: https://doi.
org/10.
1038/s41586-021-03536-w Reprinting instructions [Original Articles] BioArt original articles, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is Owned by BioArt.

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