Structural basis of noscapine activation for tubulin binding

Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain in vivo models through amechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A-O-demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a stericclash of the compound with the T5-loop of a-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite thatbinds to the colchicine site of tubu- lin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism