STM2457

For a considerable amount of time, RNA inhibition has been acknowledged as a potentially effective therapeutic intervention, and STM2457 holds the potential to expand the parameters of this field. STM2457 is an RNA inhibitor that can target and modify particular RNA molecules with exceptional specificity, providing hitherto unheard-of control over patterns of gene expression. This skill has enormous promise for treating a wide range of illnesses at their source, from genetic abnormalities to certain kinds of cancer. The molecular structure of STM2457 is shown in Figure 1.

Figure 1: The molecular structure of  STM2457.

METTL3's catalytic function is eliminated when STM2457 directly binds into the SAM-binding pocket of METTL3. Significant cytotoxicity was seen when STM2457 was treated in a panel of acute myeloid leukemia (AML) cells. Furthermore, STM2457 significantly enhanced AML cell death. Investigating the underlying mechanisms, STM2457 decreases oncogenic mRNA translation in AML cells, including SP1, BRD4, and MYC, which is dependent on m6A. STM2457 suppresses medulloblastoma and cholangiocarcinoma and restores chemosensitivity in small lung cell carcinoma, according to another research. Here, using a panel of breast cancer cells that represent three different clinical subtypes, we examined the anticancer properties of STM2457. According to our research, STM2457 treatment dramatically lowered cell viability, prevented the growth of colonies, and caused apoptosis. These results provide credence to STM2457's possible application as a breast cancer treatment agent.

 STM2457 is a strong inhibitor of METTL3 and 14 methyltransferase activity (Fig. 2A). By adjusting the dosage and length of treatment, we used MTT assays to examine the impact of STM2457 on the viability of MCF7, SKBR3, and MDA-MB-231 breast cancer cells in order to better explore the drug's potential as a therapeutic agent for breast cancer. The findings demonstrated that, depending on the dosage and length of treatment, STM2457 therapy reduced cell viability (Fig. 2B-2D). After 96 hours of treatment, cell viability was 50% lower at the highest concentration of STM2457 (20 µM) compared to the control cells (Fig. 2B-2D). Notably, after 72 and 96 hours of treatment, there were notable reductions in cell viability at concentrations of 7 µM, 10 µM, and 20 µM. Additionally, the cytotoxic effects of STM2457 increased proportionately with the length of treatment. Based on our findings, STM2457 appears to have strong cytotoxic effects on breast cancer cells, and these effects hold true for the three cell lines that we examined.

Figure 2: Effects of STM2457 on cell viability of MCF7, SKBR3, and MDA- MB-231 cells. (A) Chemical structure of N-((6-((cyclohexyl methyl)amino)methyl)imidazole[1,2-a] pyridin-2-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, STM2457. Half maximal inhibitory concentration (IC50) value against methyltransferase activity of METTL3-METTL14 complex is shown below structure. (B–D) MCF7, SKBR3, and MDA-MB-231 cells were treated with different concentrations of STM2457 for 24 h, 48 h, 72 h, and 96 h, respectively. 

STM2457 activates PARP and caspase 3 to cause apoptosis in breast cancer cells. After we first evaluated STM2457's cytotoxic effects on the viability of breast cancer cells. Next, we looked at the expression of cleaved caspase 3 and cleaved PARP, which are indicators of apoptosis, in MCF7, SKBR3, and MDA-MB-231 breast cancer cells to see how STM2457 therapy affected apoptotic cell death. STM2457-induced cleavage of PARP was observed in all three cell lines, while cleavage of caspase 3 was shown in SKBR3 and MDA-MB-231 cells, according to the results of western blotting (Fig. 3A). We did not find caspase 3 expression in MCF7 cells, which is consistent with a prior result . To learn more about how STM2457 therapy affects cell cycle progression, we conducted a cell cycle analysis. Treatment of STM2457 consistently causes cell cycle arrest in G0/G1 phase in various breast cancer cell lines, according to cell cycle analysis (Fig. 3B). To examine the level of cell apoptosis in more detail, annexin V-FITC/PI  double labeling was employed. In compared to the control group, STM2457 treatment dose-dependently increased the proportion of late-stage apoptotic cells (Annexin V-FITC and PI-positive cells) in the previously stated breast cancer cell lines (MCF7, SKBR3, and MDA-MB-231) (Fig. 3). Together, these data demonstrate that STM2457 promotes apoptosis and cell cycle arrest in breast

Figure 3: Effects of STM2457 on apoptotic signaling pathway and cell cycle arrest in MCF7, SKBR3, and MDA-MB-231 cells.  (A) Cells were treated with the indicated doses of STM2457 for 48 h and harvested.  The cleaved and total proteins of PARP and caspase 3 in whole-cell lysates were determined by immunoblotting analysis using indicated antibodies. (B) Cells were treated with the indicated doses of STM2457 for 48 h, and cell cycle distribution was analyzed using a MuseTM cell analyzer. The percentage of cells in the G0/G1, S, and G2/M phases are shown in the inset.

Using MCF7, SKBR3, and MDA-MB-231 cells, the soft agar experiment was used to assess the tumorigenic potential of breast cancer cells (Fig. 4A). According to our findings, all three cells' colonies' sizes and numbers were significantly reduced when they were treated with STM2457 in a dose-dependent manner (Fig. 4B). These results suggest that STM2457 may have therapeutic promise in the management of breast cancer.

Figure 4: Inhibitory effects of STM2457 on anchorage-independent growth of MCF7, SKBR3, and MDA-MB-231 cells. 

According to the research, STM2457 exhibits strong cytotoxic properties against cancer cells. According to our findings, all three of the breast cancer cell lines experienced a dose- and time-dependent decline in cell viability as a result of STM2457 therapy. Furthermore, the cytotoxic effects that were identified became more noticeable as STM2457 administration increased. Osteoblast apoptosis is brought on by cleaved caspase-3, cleaved PARP-1, and cleaved caspase-12 . Nevertheless, research on STM2457's impact on the stability or expression of the apoptosis-related protein in breast cancer is still lacking. The activation of caspase 3 and PARP cleavage in each of the three cell lines evaluated by us indicates that STM2457 triggered apoptosis in breast cancer cells. Furthermore, treatment with STM2457 resulted in cell cycle arrest in the G0/G1 phase, indicating that it can also cause apoptosis in breast cancer cells. According to a recent study, the ability of breast cancer cells to form colonies is suppressed when METTL3 is knocked down . We investigated the effect of the METTL3 inhibitor STM2457 on the anchorage-independent growth of three distinct subtypes of breast cancer cells. STM2457 decreased the ability of breast cancer cells to form colonies, as seen by the considerable decrease in the size and quantity of colonies formed by MCF7, SKBR3, and MDA-MB-231 cells treated with STM2457, which is consistent with METTL3 knockdown studies. All of these findings point to the possibility of STM2457 serving as a therapeutic agent for the treatment of breast cancer.

To sum up, this study shows that STM2457 inhibits clonogenicity, causes cell apoptosis, and has strong cytotoxic effects on breast cancer cells. These findings suggest that STM2457 might be suggested as a potential anticancer treatment for breast cancer. Prior to clinical translation, more research is necessary to determine its safety and efficacy in vivo.