2. Academic Validation
  3. A novel synthesised STAT3 inhibitor exerts potent anti-tumour activity by inducing lysosome-dependent cell death

A novel synthesised STAT3 inhibitor exerts potent anti-tumour activity by inducing lysosome-dependent cell death

  • Br J Pharmacol. 2025 May 13. doi: 10.1111/bph.70071.
Marvin Xuejun Xu 1 2,  Xinxin Liu 3,  Hai-Liang Zhang 4,  Hongyun Xu 1,  Xiangyu Ma 2,  Yupo Yang 1,  Chaoqun Duan 1,  Shanshun Tang 1,  Yaqing Liu 1,  Cen Li 1,  Mengfu Pei 1,  Junkai Xia 1,  Yali Yang 1,  Yanmin Guo 1,  Yang Wang 5,  Songping Luo 6,  Jianguo Ma 1,  Zhengyan Yang 1 7,  Xiao-Feng Zhu 4,  Chun-Ping Xu 1
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Small Molecular Anti-cancer Novel Drug, Henan International Joint Lab of Target Anti-cancer Drug, Henan Engineering Research Center of Target Anti-cancer Drug, Henan Ruida Bio-tech Medicine Co. Ltd, Kaifeng, China.
  • 2 Department of Hematology, Zhengzhou University Affiliated Luoyang Central Hospital, Luoyang, China.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5 Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China.
  • 6 Kaifeng Central Hospital EICU, Kaifeng, China.
  • 7 Henan International Joint Laboratory for Nuclear Protein Regulation, Department of Pathology, School of Basic Medical Sciences, Henan University, Kaifeng, China.
PMID: 40356419 DOI: 10.1111/bph.70071
Abstract

Background and purpose: Signal transducer and activator of transcription 3 (STAT3) has emerged as a promising therapeutic target for triple-negative breast Cancer (TNBC) and multiple myeloma (MM), yet no STAT3-selective drugs have been approved for clinical use.

Experimental approach: Newly synthesized compounds were screened by docking, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) to measure the binding activity with STAT3. RNA-Seq, luciferase assays, western blot and immunofluorescence assays were conducted to detect the impact of RDp002 on STAT3 signalling. CCK-8, cell cycle, Apoptosis assays and transwell were utilised to evaluate the anti-tumour activity of RDp002 in vitro. Xenograft models were used to assess the effectiveness of RDp002 in vivo. Various inhibitors were utilised to investigate how RDp002 causes tumour cell death. The human ether-à-go-go-related gene (hERG/Kv11.1) assays, blood biochemistry and acute toxicity experiments were conducted to explore the toxicity of RDp002.

Key results: RDp002 exhibited had strong affinity for STAT3 and impaired the phosphorylation of STAT3 at tyrosine 705 and serine 727 residues. RDp002 suppressed the proliferation, survival, migration, growth and metastasis of TNBC and MM cells. RDp002 inhibited tumour cell viability primarily via lysosome-dependent cell death, which can be weakened by overexpression of STAT3. The toxicity of RDp002 in vivo was minimal based on results from hERG assays, blood biochemistry analysis and acute toxicity tests.

Conclusion and implications: RDp002 is a novel STAT3 Inhibitor that exerts potent anti-tumour effects mainly by inducing lysosome-dependent cell death. RDp002 represents a promising therapeutic lead for TNBC and MM.

Keywords

RDp002; STAT3 inhibitor; lysosome‐dependent cell death; multiple myeloma (MM); triple‐negative breast cancer (TNBC).

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