Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.
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.
STAT5 is an attractive therapeutic
target for human cancers. We
report herein the discovery of a potent and selective STAT5 degrader
with strong antitumor activity in vivo. We first
obtained small-molecule ligands with sub-micromolar to low micromolar
binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal
structures of three such ligands in complex with STAT5A. We successfully
transformed these ligands into potent and selective STAT5 degraders
using the PROTAC technology with AK-2292 as the best compound. AK-2292
effectively induces degradation of STAT5A, STAT5B, and phosphorylated
STAT5 proteins in a concentration- and time-dependent manner in acute
myeloid leukemia (AML) cell lines and demonstrates excellent degradation
selectivity for STAT5 over all other STAT members. It exerts potent
and specific cell growth inhibitory activity in AML cell lines with
high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5
protein in vivo and achieves strong antitumor activity
in mice at well-tolerated dose schedules.
Signal
transducer and activator of transcription 3 (STAT3) is an
attractive cancer therapeutic target. We report herein our extensive in vitro and in vivo evaluations of SD-91,
the product of the hydrolysis of our previously reported STAT3 degrader
SD-36. SD-91 binds to STAT3 protein with a high affinity and displays
>300-fold selectivity over other STAT family protein members. SD-91
potently and effectively induces degradation of STAT3 protein and
displays a high selectivity over other STAT members and >7000 non-STAT
proteins in cells. A single administration of SD-91 selectively depletes
STAT3 protein in tumor tissues with a persistent effect. SD-91 achieves
complete and long-lasting tumor regression in the MOLM-16 xenograft
model in mice even with weekly administration. Hence, SD-91 is a potent,
highly selective, and efficacious STAT3 degrader for extensive evaluations
for the treatment of human cancers and other diseases for which STAT3
plays a key role.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.