Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment

Huang Chen; Aiwu Bian; Wenbo Zhou; Ying Miao; Jiangnan Ye; Jiahui Li; Peng He; Qiansen Zhang; Yue Sun; Zhenliang Sun; Chaowen Ti; Yihua Chen; Zhengfang Yi; Mingyao Liu

doi:10.1021/acscentsci.3c01440

Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment

ACS Cent Sci. 2024 Feb 10;10(3):579-594. doi: 10.1021/acscentsci.3c01440. eCollection 2024 Mar 27.

Authors

Huang Chen^{1

2}, Aiwu Bian^{1

2}, Wenbo Zhou^{1

2}, Ying Miao¹, Jiangnan Ye¹, Jiahui Li³, Peng He¹, Qiansen Zhang¹, Yue Sun¹, Zhenliang Sun³, Chaowen Ti¹, Yihua Chen¹, Zhengfang Yi¹, Mingyao Liu^{1

2}

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, P.R. China.
² Shanghai Yuyao Biotech Co., LTD. Shanghai 200241, China.
³ Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China.

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Unfortunately, targeting STAT3 with small molecules has proven to be very challenging, and for full activation of STAT3, the cooperative phosphorylation of both tyrosine 705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective inhibitor of STAT3 dual phosphorylation has not been developed. Here, we identified a low nanomolar potency and highly selective small-molecule STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor cell growth in vitro and achieved potent suppression of tumor growth and metastasis in vivo. More importantly, YY002 exhibited favorable pharmacokinetics, an acceptable safety profile, and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor that has advanced into phase III trials). For the mechanism, YY002 is selectively bound to the STAT3 Src Homology 2 (SH2) domain over other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial functions in STAT3-dependent cells. Collectively, this study suggests the potential of small-molecule STAT3 inhibitors as possible anticancer therapeutic agents.