Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Proteins
of the bromodomain and extra-terminal (BET) family are
epigenetics “readers” and promising therapeutic targets
for cancer and other human diseases. We describe herein a structure-guided
design of [1,4]­oxazepines as a new class of BET inhibitors and our
subsequent design, synthesis, and evaluation of proteolysis-targeting
chimeric (PROTAC) small-molecule BET degraders. Our efforts have led
to the discovery of extremely potent BET degraders, exemplified by
QCA570, which effectively induces degradation of BET proteins and
inhibits cell growth in human acute leukemia cell lines even at low
picomolar concentrations. QCA570 achieves complete and durable tumor
regression in leukemia xenograft models in mice at well-tolerated
dose-schedules. QCA570 is the most potent and efficacious BET degrader
reported to date.