By using the efficient protocol for synthesis of unsymmetrical biaryls with the ligand previously developed by our group, a novel tubulin inhibitor dxy-1-175 with anti-cancer activity was discovered. By rational design, a series of new dxy-1-175 analogues were prepared. Among them, compound 12e selectively and potently inhibited tumor growth both in vitro and in vivo. Notably, 12e effectively overcame P-gp-mediated MDR, suggesting that 12e might be useful in the treatment of drug refractory tumors.