A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Longchuan Bai; Haibin Zhou; Renqi Xu; Yujun Zhao; Krishnapriya Chinnaswamy; Donna McEachern; Jianyong Chen; Chao-Yie Yang; Zhaomin Liu; Mi Wang; Liu Liu; Hui Jiang; Bo Wen; Praveen Kumar; Jennifer L Meagher; Duxin Sun; Jeanne A Stuckey; Shaomeng Wang

doi:10.1016/j.ccell.2019.10.002

A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo

Cancer Cell. 2019 Nov 11;36(5):498-511.e17. doi: 10.1016/j.ccell.2019.10.002.

Authors

Longchuan Bai¹, Haibin Zhou¹, Renqi Xu¹, Yujun Zhao¹, Krishnapriya Chinnaswamy², Donna McEachern¹, Jianyong Chen¹, Chao-Yie Yang¹, Zhaomin Liu¹, Mi Wang¹, Liu Liu¹, Hui Jiang³, Bo Wen⁴, Praveen Kumar⁴, Jennifer L Meagher², Duxin Sun⁴, Jeanne A Stuckey⁵, Shaomeng Wang⁶

Affiliations

¹ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
² Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
³ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].

Abstract

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.

Keywords: PROTAC; SH2 domain; STAT3; c-Myc; degrader; leukemia; lymphoma; selectivity; transcriptional factor; undruggable.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Cell Cycle Checkpoints / drug effects
Cell Cycle Checkpoints / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology
Lymphoma, Large-Cell, Anaplastic / drug therapy*
Lymphoma, Large-Cell, Anaplastic / genetics
Lymphoma, Large-Cell, Anaplastic / pathology
Mice
Proteolysis / drug effects
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
STAT3 Transcription Factor
STAT3 protein, human

Grants and funding

P30 CA046592/CA/NCI NIH HHS/United States