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

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.