Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential

Antiangiogenic agents (AA) are cytostatic, and their utility in Cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of vascular endothelial growth factor receptor-2 (VEGFR2/KDR/Flk-1) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2/KDR/Flk-1 inhibitory activity (comparable to that of sunitinib) with potent antitubulin activity (comparable to that of combretastatin A-4 (CA)) in a single molecule, with GI50 values of 10(-7) M across the entire NCI 60 tumor cell panel. It potently inhibited tubulin assembly and circumvented the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to antimicrotubule agents. The compound is freely water-soluble as its HCl salt and afforded excellent antitumor activity in vivo, superior to docetaxel, sunitinib, or Temozolomide, without any toxicity.

Antitubulin; VEGFR2 inhibition; antiangiogenic; antimitotic; combination chemotherapy.