Abstract 7123: QW-5-70 targets the colchicine site to overcome multidrug resistance and shows potent antitumor activities

Abstract Drug resistance driven by efflux transporters and altered tubulin dynamics limits the clinical efficacy of taxanes and vincristine in high-risk neuroblastoma (NB) and castration-resistant prostate cancer (CRPC). We developed QW-5-70, a colchicine-binding-site inhibitor (CBSI), engineered to retain subnanomolar potency in both parental and drug-resistant cancer cells by evading P-glycoprotein (P-gp)-mediated efflux. QW-5-70 binds to the colchicine site, inhibits tubulin polymerization, disrupts microtubule networks, and induces mitotic arrest. Across a panel of NB and prostate cancer lines, QW-5-70 maintained subnanomolar activity and remained effective in vincristine-resistant BE2C/VCR and paclitaxel-resistant PC-3/TxR cells. Unlike vincristine and paclitaxel, its activity was unchanged by co-treatment with verapamil, suggesting its ability to circumvent P-gp-mediated drug 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 testing revealed strong quantitative synergy with DFMO in viability assays and marked increases in apoptosis with reduced clonogenic survival when paired with DFMO or the Aurora A inhibitor MLN8237. Collectively, QW-5-70 is a potent CBSI that circumvents P-gp-associated resistance, triggers mitotic arrest and apoptosis, and achieves robust antitumor activity in multidrug-resistant tumor models with acceptable tolerability, supporting its further preclinical development alone and in combination with other drugs. Citation Format: Yang Xie, Ruida Hou, Najah Albadari, Hao Chen, Darcie J. Miller, Judith Quadrozzi Gruntz, Michael L. Oldham, Mir Shahriar Kamal, Jianxiong Jiang, Zhongzhi Wu, Duane D. Miller, Wei Li. QW-5-70 targets the colchicine site to overcome multidrug resistance and shows potent antitumor activities abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7123.