QW-5-70

Drug resistance driven by efflux transporters and altered tubulin dynamics limits the clinical efficacy of taxanes and vincristine in high-risk neuroblastoma and castration-resistant prostate cancer. We developed QW-5-70, a colchicine binding site inhibitor (CBSI), engineered to retain low-nanomolar potency in both parental and drug-resistant cancer cells by showing minimal dependence on P-glycoprotein (P-gp)–mediated efflux. QW-5-70 binds to the colchicine site on tubulin, inhibits tubulin polymerization, disrupts microtubule networks, and induces mitotic arrest. Across a panel of neuroblastoma and prostate cancer lines, QW-5-70 maintained low-nanomolar activity and remained effective in vincristine-resistant BE2C/VCR and paclitaxel-resistant PC-3/TxR cells. Unlike vincristine and paclitaxel, the activity and intracellular accumulation of QW-5-70 were unaffected by pharmacologic or genetic inhibition of P-gp, indicating effective circumvention of efflux-mediated resistance. In vitro, QW-5-70 significantly reduced colony formation and impaired migration in both parental and resistant cancer cells and induced G2–M cell-cycle arrest and mitochondrial apoptosis. In vivo, QW-5-70 significantly suppressed tumor growth in drug-resistant PC-3/TxR and BE2C/VCR xenografts, with modest weight loss and no evident histopathology in the major organs. Combination studies revealed combination index–defined synergistic interactions at selected dose pairs with the ornithine decarboxylase inhibitor α-difluoromethylornithine and enhanced apoptotic and clonogenic suppression when combined with the Aurora A kinase inhibitor MLN8237. Collectively, QW-5-70 is a potent CBSI that circumvents P-gp–associated resistance, triggers mitotic arrest and apoptosis, and achieves significant antitumor activity in multidrug-resistant tumor models with acceptable tolerability, supporting its further preclinical development alone and in combination with other drugs.