A collection of 9050 natural products, their derivatives, and mimetics, was virtually screened against the human Atg3-Atg8 (Atg - autophagy) binding scaffold. By blocking this interaction, the lipidation of Atg8 does not occur and the formation of autophagosomes is inhibited. Forty-three (43) potential ligands were tested using enhanced Green Fluorescent Protein (eGFP) tagged LC3, the human ortholog of Atg8, in MCF7 breast cancer cells. Three hits showed single digit µM IC₅₀ values with AT110, an isoflavone derivative, being the best at 1.2 ± 0.6 µM. Molecular modelling against Atg8 in conjunction with structural activity relationship (SAR) strongly supports the binding to this target. Testing in a panel of cancer cell lines showed little cytotoxic effect as compared to chloroquine. However, same concentration of AT110 was shown to be toxic to young zebrafish embryos. This can be explained in terms of the autophagy process being very active in the zebrafish embryos rendering them susceptible to AT110 whereas in the cancer cells tested the autophagy is not usually active. Nevertheless, AT110 blocks autophagy flux in the zebrafish confirming that the ligand is modulating autophagy. A small molecule non-cytotoxic autophagy inhibitor would open the door for adjunct therapies to bolster many established anticancer drugs, reducing their efficacious concentration thus limiting undesirable site effects. In addition, since many cancer types rely on the autophagy mechanism to survive a therapeutic regime, recurrence can potentially be reduced. The discovery of AT110 is an important step in establishing such an adjunct therapy.

的9050的天然产物，它们的衍生物，和模拟物的集合，实际上被筛选针对人ATG3-的Atg8 - （署理一个û吨OPHA克结合支架Y）。通过阻断这种相互作用，Atg8 的脂化不会发生，自噬体的形成受到抑制。使用增强型绿色荧光蛋白 (eGFP) 标记的 LC3（Atg8 的人类直系同源物）在 MCF7 乳腺癌细胞中测试了四十三 (43) 个潜在配体。三个命中显示个位数 µM IC ₅₀AT110（一种异黄酮衍生物）的值在 1.2 ± 0.6 µM 时最佳。针对 Atg8 的分子建模结合结构活性关系 (SAR) 强烈支持与该目标的结合。与氯喹相比，在一组癌细胞系中进行的测试显示几乎没有细胞毒性作用。然而，相同浓度的 AT110 被证明对年轻的斑马鱼胚胎有毒。这可以解释为斑马鱼胚胎中的自噬过程非常活跃，使它们对 AT110 敏感，而在测试的癌细胞中，自噬通常不活跃。然而，AT110 阻断了斑马鱼的自噬通量，证实了配体正在调节自噬。一种小分子非细胞毒性自噬抑制剂将为辅助疗法打开大门，以支持许多已建立的抗癌药物，降低它们的有效浓度，从而限制不良的位点效应。此外，由于许多癌症类型依赖自噬机制在治疗方案中存活下来，因此有可能减少复发。AT110 的发现是建立这种辅助疗法的重要一步。