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BET family inhibitor JQ1 for studying protein homeostasis

JQ1 is a potent bromodomain and extraterminal protein (BET) inhibitor with high specificity for acetyl-lysine recognition motifs found in BET family (BRD2, BRD3, BRD4, BRDT). JQ1 engages the bromodomain pocket and competes with acetylated peptide binding to displace BET proteins from chromatin, disrupting transcription.

Proteolysis targeting chimeras (PROTACs) are used to direct proteins to proteasomes. It consists of a small ligand, with high affinity for the target protein, that is paired with another ligand that recruits E3 ubiquitin ligase. Once a ternary complex of the PROTAC and protein target occurs, the target protein is destined for ubiquitylation and degradation.

Multiplexed proteome dynamics profiling (mPDP) is a spectrometry (LC-MS/MS)-based method, combining dynamic SILAC labeling with isobaric mass tagging. This technique allows for simultaneous analysis of alterations in protein degradation and synthesis in a single mass spectrometric experiment, considering biological replicates and multiple treatment conditions.

A bromodomain and extra-terminal domain (BET)-PROTAC was synthesized, by coupling JQ1 to a peptidomimetic of the HIF1A hydroxyproline-containing sequence motif that binds Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. The effect of JQ1-PROTAC was compared with JQ1 alone, where mPDP allows to distinguish between the two. 

Please refer to the paper for more more details: Savitski et al., 2018.

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