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

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 are anticipated to have wide future
applicability.