Research has shown that the PI3K δ inhibitor compound CHMFL-PI3KD-317 exhibits good in vivo efficacy against B-cell associated tumors, such as acute myeloid leukemia (AML). This article describes a bioelectronic isosubstitution method for developing novel 2-aminopyridine PI3K δ inhibitors. Through studying the structure-activity relationship and biological evaluation of similar structures, it was determined that compound MR3278 is an effective PI3K δ inhibitor with certain anti proliferative effects on blood cells in vitro.

This article chooses MR3278 to study its anti proliferative activity against human cancer cell lines, with Idelalisib and PI-103 as positive controls. As shown in the figure, MR3278 has moderate inhibitory activity on cancer blood cells, with IC50 values of 2.6 and 18.9 μ M. However, the widely recognized highly selective PI3K δ inhibitor Idelalisib has not shown significant anti proliferative effects on most cell lines. On the contrary, the pan PI3K inhibitor PI-103 showed stronger anti proliferative effects than MR3278 and Idelalisib. This may be related to the fact that PI3K δ inhibitors may mediate anti-tumor effects through the cancer microenvironment.

Due to MR3278's superior anti proliferative activity against AML cells, this compound was selected for further investigation of its effects on cell apoptosis and cell cycle. As shown in the figure, MR3278 induces significant apoptosis of Mv-4-11 cells in a dose-dependent manner. As the concentration of MR3278 increased from 1 μ M to 10 μ M, the percentage of apoptotic cells increased from 3.85% to 31.31%. Cell cycle analysis showed that MR3278 dose dependently arrested the cell cycle in the G2/M phase.

After confirming the effects of MR3278 on PI3K δ kinase activity, anti proliferation, cell cycle, and apoptosis, its impact on the expression of PI3K pathway related proteins in Mv-4-11 cells was detected by Western blot (WB). As shown in the figure, with the increase of MR3278 concentration, the phosphorylation level of AKT gradually decreases, indicating that the activity of PI3K pathway in Mv-4-11 cells is blocked. In summary, all these results further confirm the effective activity of MR3278 in inhibiting PI3K δ kinase activity, blocking cell cycle, and inducing cell apoptosis.

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