Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure

Klisyri (KX01) is a dual tubulin/Src
protein inhibitor that has
shown potential therapeutic effects in several tumor models. However,
a phase II clinical trial in patients with bone-metastatic castration-resistant
prostate cancer was halted because of lack of efficacy. We previously
reported that KX01 binds to the colchicine site of β-tubulin
and its morpholine group lies close to α-tubulin’s surface.
Thus, we hypothesized that enhancing the interaction of KX01 with
α-tubulin could increase tubulin inhibition and synthesized
a series of KX01 derivatives directed by docking studies. Among these
derivatives, 8a exhibited more than 10-fold antiproliferation
activity in several tumor cells than KX01 and significantly improved in vivo antitumor effects. The X-ray crystal structure suggested
that 8a both bound to the colchicine site and extended
into the interior of α-tubulin to form potent interactions,
presenting a novel binding mode. A potential clinical candidate for
cancer therapy was identified in this study.