Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xlbright and pAktbright cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38bright cells followed apoptosis (IC50: 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo.

中文翻译：

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咪唑并[1,2-b]吡唑-7-羧酰胺衍生物诱导未成熟髓样细胞（如急性髓样白血病和髓样来源的抑制细胞）的分化偶联凋亡。

化学疗法诱导的未成熟骨髓祖细胞的分化，例如急性髓细胞白血病（AML）细胞或骨髓源性抑制细胞（MDSC），仍然是临床医生面临的挑战。在HL-60细胞上测试我们的咪唑并[1,2-b]吡唑-7-羧酰胺衍生物，我们获得了ERK磷酸化，作为对治疗的早期存活反应，随后增加了Bcl-xlbright和pAktbright细胞的百分比。诱导Vav1和AP-1复合物后，细胞分化的驱动因子FOS，JUN，JUNB和JUND以浓度和时间依赖性方式升高。作为粒细胞分化的证据，细胞保持非粘附状态，CD33的表达下降。处理后，HL-60细胞的粒度，CD11b表达和MPO活性增加。最后，线粒体去极化，caspase-3的活化，Z-DEVD-aLUC的裂解，sub-G1群体的出现以及乳酸-脱氢酶向上清液的渗漏表明，HL-60细胞的生存能力受到阻碍。我们证实离体治疗后，CD11b的增加和CD33 +，CD7 +，CD206 +和CD38bright细胞的凋亡（IC50：80 nM）减少，表明我们的候选药物对人患者来源的AML细胞具有分化作用（IC50：80 nM）。我们的化合物从小鼠4T1乳腺癌模型中体内还原了CD11b + / Ly6C +和CD11b + / Ly6G +脾脏MDSC。我们证实离体治疗后，CD11b的增加和CD33 +，CD7 +，CD206 +和CD38bright细胞的凋亡（IC50：80 nM）减少，表明我们的候选药物对人患者来源的AML细胞具有分化作用（IC50：80 nM）。我们的化合物从小鼠4T1乳腺癌模型中体内还原了CD11b + / Ly6C +和CD11b + / Ly6G +脾脏MDSC。我们证实离体治疗后，CD11b的增加和CD33 +，CD7 +，CD206 +和CD38bright细胞的凋亡（IC50：80 nM）减少，表明我们的候选药物对人患者来源的AML细胞具有分化作用（IC50：80 nM）。我们的化合物从鼠4T1乳腺癌模型中体内还原了CD11b + / Ly6C +和CD11b + / Ly6G +脾脏MDSC。