Synthetic homoisoflavane derivatives suppress the growth of colorectal cancer cells by disturbing microtubule dynamics

Microtubules, composed of tubulin proteins, have a crucial role in various cellular processes, including cell cycle regulation. The dynamic instability of microtubules has been an attractive target for cancer therapy. This study investigated two potent anticancer drug candidates, homoisoflavane derivatives SH-19021 and SHA-035, and evaluated their potential as microtubule-targeting agents (MTAs) in human colorectal cancer cells. At early time points, both SH-19021 and SHA-035 induced G2/M phase arrest. They altered the expression of multiple cell cycle-related genes, notably downregulating tubulin mRNA levels, leading to reduced cell viability and apoptosis. To further explore their mechanism of action, we conducted in silico docking studies, which demonstrated the potential of SH-19021 and SHA-035 as tubulin inhibitors. Both compounds were shown to bind directly to tubulin proteins, inhibiting microtubule polymerization in vitro and disrupting microtubule structures in colorectal cancer cells. Additionally, SH-19021 exhibited antitumor activity in a mouse xenograft model implanted with HCT116 cells. These findings suggest that SH-19021 and SHA-035 are novel and potent microtubule destabilizers with promising potential for cancer treatment.