A novel tubulin inhibitor, No.07, shows anti-cancer and anti-metastatic effects in colon cancer and tumoroids

Abstract

Colorectal cancer is a highly metastatic disease and the second leading cause of cancer-related death worldwide. Despite the use of various treatment strategies, including chemotherapy and targeted therapy, challenges such as toxicity, drug resistance, and poor response indicate the critical need for new therapeutic agents. Microtubule target agents are one of the major treatment options for chemotherapy in various cancer patients. However, most of these agents are substrates of the MDR1 protein, which leads to the development of multidrug resistance, significantly limiting their effectiveness. Therefore, the development of new drugs is being actively pursued. In this study, we synthesized a novel compound, No.07, which demonstrates significant anti-cancer activity in 3D spheroid models, patient-derived colon cancer organoid models, and mice xenograft models. No.07 directly binds to tubulin dimers, interfering with microtubule polymerization and thereby disrupting tubulin dynamics, ultimately inducing mitotic arrest. Furthermore, No.07 increases mitochondria reactive oxygen species level, leading to the inactivation of the RAF-MEK-ERK signaling cascade, which consequently inhibits metastasis. Notably, Swiss ADME predictions suggest that No.07 is not a substrate of MDR1 and can cross the blood-brain barrier, unlike other microtubule target agents that are limited by MDR1-mediated drug resistance and poor brain penetration. Additionally, experiments using multidrug-resistant cell lines confirmed that No.07 effectively overcomes multidrug resistance, providing a significant improvement over traditionally used chemotherapy agents. In conclusion, No.07 has the potential to address the limitations of existing treatments as a novel therapeutic option.