Using a pharmacophore model based on the experimental structure of AKT-1, we recently identified the compound STL1 (ZINC2429155) as an allosteric inhibitor of AKT-1. STL1, was able to reduce Ser473 phosphorylation, thus inhibiting the PI₃K/AKT pathway. Moreover, we demonstrated that the flavonoid quercetin downregulated the phosphorylated and active form of AKT. However, in this case, quercetin inhibited the PI₃K/AKT pathway by directly binding the kinases CK2 and PI₃K. In the present work, we investigated the antiproliferative effects of the co-treatment quercetin plus STL1 in HG-3 cells, derived from a patient affected by chronic lymphocytic leukemia. Quercetin and STL1 in the mono-treatment maintained the capacity to inhibit AKT phosphorylation on Ser473, but did not significantly reduce cell viability. On the contrary, they activated a protective form of autophagy. When the HG-3 cells were co-treated with quercetin and STL1, their association synergistically (combination index < 1) inhibited cell growth and induced apoptosis. The combined treatment caused the switch from protective to non-protective autophagy. This work demonstrated that cytotoxicity could be enhanced in a drug-resistant cell line by combining the effects of different inhibitors acting in concert on PI₃K and AKT kinases.

中文翻译：

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STL1，一种新的 AKT 抑制剂，与类黄酮槲皮素协同作用，增强慢性淋巴细胞白血病细胞系的细胞死亡

使用基于 AKT-1 实验结构的药效团模型，我们最近将化合物 STL1 (ZINC2429155) 鉴定为 AKT-1 的变构抑制剂。STL1 能够降低 Ser473 磷酸化，从而抑制 PI ₃ K/AKT 通路。此外，我们证明类黄酮槲皮素下调了 AKT 的磷酸化和活性形式。然而，在这种情况下，槲皮素通过直接结合激酶 CK2 和 PI _{3来抑制 PI 3 K/AKT 通路}K. 在目前的工作中，我们研究了槲皮素和 STL1 联合治疗对 HG-3 细胞的抗增殖作用，该细胞来自一名受慢性淋巴细胞白血病影响的患者。单一处理中的槲皮素和 STL1 保持抑制 Ser473 上 AKT 磷酸化的能力，但不会显着降低细胞活力。相反，它们激活了一种保护性的自噬形式。当 HG-3 细胞与槲皮素和 STL1 共同处理时，它们的结合协同作用（组合指数 < 1）抑制细胞生长并诱导细胞凋亡。联合治疗导致从保护性自噬转变为非保护性自噬。_{这项工作表明，通过结合对 PI 3}协同作用的不同抑制剂的作用，可以增强耐药细胞系的细胞毒性K 和 AKT 激酶。