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,