目的 研究LZ-106對間變性淋巴瘤激酶（ALK）激酶活性的抑制作用，及對ALK陽性細胞的生長抑制作用。方法 采用分子對接模擬LZ-106與ALK的結(jié)合，通過體外激酶活性實驗檢測其對ALK激酶活性的影響，通過CCK-8實驗檢測其對H2228細胞的生長抑制作用，通過Annexin V/PI細胞凋亡實驗檢測其對H2228細胞的凋亡作用，通過Western blotting檢測其對H2228細胞p-ALK及下游信號通路關(guān)鍵激酶表達的影響。結(jié)果 LZ-106能抑制ALK激酶活性，半數(shù)抑制濃度（IC₅₀）為（15.51±2.09）nmol/L，其能顯著抑制H2228細胞存活率，并能濃度相關(guān)性地誘導(dǎo)細胞凋亡。Western blotting實驗顯示LZ-106可以顯著抑制p-ALK、p-蛋白激酶B（Akt）及p-信號轉(zhuǎn)導(dǎo)因子和轉(zhuǎn)錄激活因子3（STAT3）的表達，且Akt及STAT3激活劑可以明顯削弱LZ-106的凋亡誘導(dǎo)作用。結(jié)論 LZ-106顯著抑制ALK激酶活性，誘導(dǎo)ALK陽性細胞凋亡，激活A(yù)kt及STAT3可以逆轉(zhuǎn)LZ-106所致的細胞凋亡。

Objective To study the inhibitory effect of LZ-106 on ALK activity and growth inhibition of ALK positive cells. Methods The binding of LZ-106 to ALK was simulated by molecular docking, its effect on ALK kinase activity was detected by in vitro kinase activity assay, its growth inhibition effect on H2228 cells was detected by CCK-8 assay, and its apoptosis effect on H2228 cells was detected by Annexin V/PI apoptosis assay. Western blotting was used to detect its effects on the expression of p-ALK and key kinases in the downstream signaling pathway of H2228 cells. Results LZ-106 can inhibit the activity of ALK kinase with IC₅₀ of 15.51 ± 2.09 nmol/L, which can significantly inhibit the survival rate of H2228 cells and induce cell apoptosis in a concentration-dependent manner. Western blotting experiments showed that LZ-106 could significantly inhibit the expression of p-ALK, p-Akt, and p-STAT3, and Akt and STAT3 activators could significantly weaken the apoptosis-inducing effect of LZ-106. Conclusion LZ-106 significantly inhibits ALK kinase activity and induces apoptosis of ALK-positive cells. Activation of Akt and STAT3 can reverse the apoptosis caused by LZ-106.

R966

江蘇省自然科學(xué)基金資助項目（BK20151443），江蘇省中醫(yī)院院級課題（Y20038）