死亡受体 (DR) 网络由死亡诱导信号复合物 (DISC) 和复合物 II 的组装控制。小分子 FLIPins（FLIP 相互作用蛋白）家族的开发是为了靶向 caspase-8/c-FLIPL 异二聚体。研究表明，在用死亡配体 (DL)（例如 CD95L 和 TRAIL）刺激后，FLIPin 化合物可促进 DISC 处的细胞凋亡和 caspase-8 激活。为了进一步研究 FLIPin 化合物在 DL 介导的细胞死亡反应中的作用，我们分析了它们与 DL 和 SMAC 模拟物治疗相结合的效果。研究发现，FLIPins 可增强急性髓系白血病 (AML)、结肠癌细胞和胰腺癌细胞中 DL 和 SMAC 模拟物诱导的细胞活力丧失和细胞死亡。 FLIPins 通过增加复合物 II 的形成来增强 DL/BV6 诱导的细胞凋亡和 DL/BV6/zVAD-fmk 诱导的坏死性凋亡。我们的结果表明，靶向 caspase-8/c-FLIPL 异二聚体在增强 DL/SMAC 模拟物共刺激诱导的细胞死亡方面发挥着重要作用，并为靶向 DR 网络开辟了新的治疗策略。版权所有 © 2024 Hillert-Richter, König 、伊万尼森科、莱因霍尔德和拉夫里克。

Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIPL heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL. To further investigate the role of FLIPin compounds in the DL-mediated cell death response, we analyzed their effects in combination with DLs and SMAC mimetics treatment. FLIPins were found to enhance cell viability loss and cell death induced by DL and SMAC mimetics in acute myeloid leukemia (AML), colon and pancreatic cancer cells. FLIPins enhanced both DL/BV6-induced apoptosis and DL/BV6/zVAD-fmk-induced necroptosis via an increase in complex II formation. Our results indicate that targeting the caspase-8/c-FLIPL heterodimer plays a prominent role in enhancing cell death induced by co-stimulation of DL/SMAC mimetics and opens new therapeutic strategies for targeting DR networks.Copyright © 2024 Hillert-Richter, König, Ivanisenko, Reinhold and Lavrik.