Procaspase-8 activation at the death-inducing signaling complex (DISC) triggers extrinsic apoptotic pathway. Procaspase-8 activation takes place in the death effector domain (DED) filaments and is regulated by c-FLIP proteins, in particular, by the long isoform c-FLIPL. Recently, the first-in-class chemical probe targeting the caspase-8/c-FLIPL heterodimer was reported. This rationally designed small molecule, FLIPin, enhances caspase-8 activity after initial heterodimer processing. Here, we used a kinetic mathematical model to gain an insight into the mechanisms of FLIPin action in a complex with DISC, in particular, to unravel the effects of FLIPin at different stoichiometry and composition of the DED filament. Analysis of this model has identified the optimal c-FLIPL to procaspase-8 ratios in different cellular landscapes favoring the activity of FLIPin. We predicted that the activity FLIPin is regulated via different mechanisms upon c-FLIPL downregulation or upregulation. Our study demonstrates that a combination of mathematical modeling with system pharmacology allows development of more efficient therapeutic approaches and prediction of optimal treatment strategies.

中文翻译：

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数学建模揭示了 DED 长丝组成在靶向 Caspase-8/c-FLIPL 异二聚体的小分子的影响中的重要性

Procaspase-8 在死亡诱导信号复合体 (DISC) 处的激活触发外源性凋亡途径。Procaspase-8 激活发生在死亡效应结构域 (DED) 细丝中，并受 c-FLIP 蛋白，特别是长同种型 c-FLIPL 的调节。最近，报道了针对 caspase-8/c-FLIPL 异二聚体的一流化学探针。这种设计合理的小分子 FLIPin 在初始异二聚体加工后增强了 caspase-8 的活性。在这里，我们使用动力学数学模型深入了解 FLIPin 在 DISC 复合物中的作用机制，特别是揭示 FLIPin 在不同化学计量和 DED 灯丝组成下的影响。对该模型的分析已经确定了有利于 FLIPin 活性的不同细胞环境中的最佳 c-FLIPL 与 procaspase-8 比率。我们预测活性 FLIPin 在 c-FLIPL 下调或上调时通过不同的机制进行调节。我们的研究表明，数学建模与系统药理学相结合，可以开发更有效的治疗方法并预测最佳治疗策略。