SCHEMBL4796824: a multifaceted antitumor agent targeting microtubule dynamics, DNA damage, and Wnt/β-catenin signaling in ovarian cancer cells

SCHEMBL4796824, a BPR0L075 derivative with antitumor properties, targets tubulin's colchicine binding site and induces DNA damage response in ovarian cancer. Cell counting kit-8 (CCK-8) assay confirmed its anti-proliferative effects, while wound healing and transwell assays demonstrated inhibition of migration and invasion. Flow cytometry showed G2 phase arrest. Molecular docking and immunofluorescence revealed microtubule depolymerization via tubulin binding, analogy with BPR0L075. Real-time qPCR and western blot analysis indicated activation of ATM/Chk2 and ATR/Chk1 pathways by SCHEMBL4796824. Senescence-associated-β-galactosidase (SA-β-gal) staining showed senescence induction. Molecular docking studies suggested potential interaction with CTNNB1. Crucially, functional assays demonstrated inhibition of the Wnt/β-catenin pathway, as evidenced by downregulation of β-catenin and c-MYC. The β-catenin agonist reversed SCHEMBL4796824-induced DNA damage and senescence, establishing a causal link to the observed phenotypes. Notably, these effects were more pronounced in c-MYC amplified SK-OV-3 cells. In summary, SCHEMBL4796824 disrupts the canonical Wnt/β-catenin signaling, inducing DNA damage, and inhibits the Wnt/β-catenin/c-MYC axis, triggering cellular senescence in a pathway-dependent manner, hinting at a novel therapeutic approach.