# Small-molecule STAT3 degraders

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $643,055

## Abstract

Signal transducers and activator of transcription 3 (STAT3) is frequently activated in human cancers and
aberrant activation of STAT3 signaling is involved in tumor initiation, progression, drug resistance and immune
evasion. Thus, STAT3 has been considered to be a highly attractive cancer therapeutic target. However,
discovery and development of highly potent and selective small-molecule inhibitors of STAT3 have proven to
be very challenging for a number of reasons.
 The proteolysis targeting chimera (PROTAC) strategy has recently gained tremendous momentum for its
promise for the discovery and development of an entirely different type of new therapeutics through inducing
targeted protein degradation. We hypothesize that PROTAC STAT3 degraders (hereafter called STAT3
degraders) may be much more effective than STAT3 inhibitors in inhibition of STAT3 transcriptional activity.
To date, no STAT3 degraders have been reported.
 Based upon a class of highly potent STAT3 inhibitors, we have designed and developed the first-in-class
STAT3 degraders, as exemplified by our lead compound SD-36. SD-36 is highly potent and effective in
inducing the degradation of STAT3 protein and demonstrates an absolute selectivity over other STAT
members and all other >5,000 proteins examined. Degradation of STAT3 by SD-36 results in a robust
suppression of STAT3 transcription activity and down-regulation of STAT3 transcription network in tumor
cells. Our initial screening demonstrated that SD-36 inhibits the growth of a subset of AML and ALCL cell lines
that express high levels of p-STAT3 (Y705). Our pharmacodynamic (PD) studies showed that a single
intravenous administration of SD-36 is capable of reducing STAT3 protein by >90%, with the effect persisted
for more than 3 days. SD-36 achieves complete tumor regression in multiple xenograft models in mice at well
tolerate doss-schedules. Our data demonstrate that degradation of STAT3 protein is a highly promising
cancer therapeutic strategy.
 Based upon our compelling preliminary data, we propose to design, synthesize and develop highly potent
small-molecule STAT3 degraders as a new class of therapies for the treatment of human cancer and to
elucidate their mechanism of action. In addition to performance of extensive evaluations of SD-36 in vitro and
in vivo, we will further optimize SD-36 for potency and efficacy and address any weaknesses we uncover for
SD-36. Our goal is to select one or more highly potent and optimized STAT3 degrader for advanced
preclinical development for the treatment of human cancers with activated STAT3.

## Key facts

- **NIH application ID:** 9865896
- **Project number:** 1R01CA244509-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SHAOMENG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $643,055
- **Award type:** 1
- **Project period:** 2019-12-06 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865896

## Citation

> US National Institutes of Health, RePORTER application 9865896, Small-molecule STAT3 degraders (1R01CA244509-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9865896. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*