Microtubule-targeted drugs are now indispensable for the
therapy of various
cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) -ethyl]-9-[(
pyridine-3-ylmethyl)amino]pyrido[2',1':2,3]imida-zo[4,5-c]isoquinolin-5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited
tubulin polymerization significantly both in
tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified
tubulin directly, with the K(D) value of 10.6 μM. The binding of MT119 in turn caused
tubulin conformational changes as evidenced by the quenched
tryptophan fluorescence, the reduction of the
bis-ANS reactivity and the decreased
DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to
tubulin at its
colchicine site. Consequently, by inhibiting
tubulin polymerization, MT119 arrested different
tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to
vincristine-,
adriamycin- or
mitoxantrone-resistant
cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of
colchicine-site-targeted inhibitors against
tubulin polymerization, which might be a promising starting point for future
cancer therapeutics.