Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

Signal transducer and activator of transcription 3 (STAT3)
is a
transcription factor and an attractive therapeutic target for cancer
and other human diseases. Despite 20 years of persistent research
efforts, targeting STAT3 has been very challenging. We report herein
the structure-based discovery of potent small-molecule STAT3 degraders
based upon the proteolysis targeting chimera (PROTAC) concept. We
first designed SI-109 as a potent, small-molecule inhibitor of the
STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase
and SI-109, we obtained a series of potent PROTAC STAT3 degraders,
exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low
nanomolar concentrations in cells and fails to degrade other STAT
proteins. SD-36 achieves nanomolar cell growth inhibitory activity
in leukemia and lymphoma cell lines with high levels of phosphorylated
STAT3. A single dose of SD-36 results in complete STAT3 protein degradation
in xenograft tumor tissue and normal mouse tissues. SD-36 achieves
complete and long-lasting tumor regression in the Molm-16 xenograft
tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective,
and efficacious STAT3 degrader.