Impact of target warhead and linkage vector on inducing protein degradation: comparison of Bromodomain and Extra-Terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds

Kwok Ho Chan, Michael Zengerle, Andrea Testa, Alessio Ciulli (Lead / Corresponding author)

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The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs, and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders is anticipated to have wide future applicability.
Original languageEnglish
Pages (from-to)504-513
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number2
Early online date8 Jun 2017
Publication statusPublished - 25 Jan 2018



  • protein degradation
  • bromodomain
  • cooperativity
  • acute myeloid leukemia

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