Dissecting DISC regulation via pharmacological targeting of caspase-8/c-FLIP_L heterodimer.

ABSTRACT: Pharmacological targeting via small molecule-based chemical probes has recently acquired an emerging importance as a valuable tool to delineate molecular mechanisms. Induction of apoptosis via CD95/Fas and TRAIL-R1/2 is triggered by the formation of the death-inducing signaling complex (DISC). Caspase-8 activation at the DISC is largely controlled by c-FLIP proteins. However molecular mechanisms of this control have just started to be uncovered. In this study we report the first-in-class chemical probe targeting c-FLIP_L in the heterodimer caspase-8/c-FLIP_L. This rationally designed small molecule was aimed to imitate the closed conformation of the caspase-8 L2' loop and thereby increase caspase-8 activity after initial processing of the heterodimer. In accordance with

SUBMITTER: Hillert LK 

PROVIDER: S-EPMC7308354 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature