Mathematical Modeling Reveals the Importance of the DED Filament Composition in the Effects of Small Molecules Targeting Caspase-8/c-FLIP_L Heterodimer

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N. V. Ivanisenko^1,a and I. N. Lavrik^1,2,b*

¹Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia

²Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany

^* To whom correspondence should be addressed.

Received July 17, 2020; Revised July 24, 2020; Accepted July 24, 2020

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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-FLIP_L. Recently, the first-in-class chemical probe targeting the caspase-8/c-FLIP_L 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-FLIP_L 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-FLIP_L 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.

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KEY WORDS: apoptosis, DISC, caspase-8, FLIPin, DED, death receptors

DOI: 10.1134/S0006297920100028

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