Dimeric natural product panepocyclinol A inhibits STAT3 via di-covalent modification
Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma <i>in vitro</i> and <i>in vivo,</i> especially those with constitutively activated STAT3 or STAT3<sup>Y640F</sup>. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.
Authors
- Fei Xia (ORCID: https://orcid.org/0000-0001-9131-8417)
- Cai‐Hong Yun (ORCID: https://orcid.org/0000-0002-5880-8307)
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Lei Zhang (ORCID: https://orcid.org/0000-0001-9031-4318)
- Yanling Wei (ORCID: https://orcid.org/0000-0002-3307-3092)
- Wenhua Lian
- Fu Gui (ORCID: https://orcid.org/0000-0001-8329-7118)
- Yiqiu Wang (ORCID: https://orcid.org/0000-0002-3175-9410)
- Qingyan Xu (ORCID: https://orcid.org/0000-0001-9789-7886)
- Sujie Zhu (ORCID: https://orcid.org/0000-0001-6488-9644)
- Lanfen Chen (ORCID: https://orcid.org/0000-0002-9413-1284)
- Yunzhan Li
- Qihong Deng (ORCID: https://orcid.org/0000-0001-9824-3534)
- Dawang Zhou
- Li Li (ORCID: https://orcid.org/0000-0002-7720-6731)
- Jianming Zhang (ORCID: https://orcid.org/0000-0002-4278-0805)
- Xiaoyang Li (ORCID: https://orcid.org/0000-0003-3741-3688)
- Fei Gao (ORCID: https://orcid.org/0000-0003-4415-6165)
- Xiaobing Wu (ORCID: https://orcid.org/0000-0002-0118-3908)
- Zhiyu Hu (ORCID: https://orcid.org/0000-0003-0181-0083)
- Yuezhou Wang (ORCID: https://orcid.org/0000-0003-0851-5351)
Institutions
- Xiamen University (CN)
- Peking University (CN)
- New York University Shanghai (CN)
- First Affiliated Hospital of Xiamen University (CN)
- Shanghai Advanced Research Institute (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Acta Pharmaceutica Sinica B
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1016/j.apsb.2024.10.001
- Citations
- 3
- Primary Topic
- Bioactive Compounds and Antitumor Agents
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- New York University Shanghai
- National Natural Science Foundation of China
- Ministry of Education of the People's Republic of China
- East China Normal University
- Xiamen University
- Xiamen Southern Oceanographic Center
- Fundamental Research Funds for the Central Universities