Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound as an inhibitor of the ATG12-ATG3 protein–protein interaction. We focused on the systematic modification of the original hit , a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein–protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

中文翻译：

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Atg12-Atg3蛋白相互作用小分子抑制剂的构效关系研究


自噬是一种分解代谢过程，在癌症晚期发挥着关键作用，它通过提供营养来维持肿瘤细胞的稳态和生长。自噬还被描述为支持替代的细胞运输途径，提供非典型的自噬依赖性炎症细胞因子分泌机制。因此，自噬抑制剂在治疗癌症和急性炎症方面具有巨大潜力。在我们的研究中，我们确定化合物是 ATG12-ATG3 蛋白质-蛋白质相互作用的抑制剂。我们专注于对最初的酪蛋白激酶 2 (CK2) 抑制剂进行系统修饰，以寻找 ATG12-ATG3 蛋白质相互作用的有效干扰物。对命中结构的系统修饰使我们获得了大量保持其 ATG12-ATG3 抑制活性的化合物，这可以作为设计具有不同治疗应用的新化合物的可行起点。