Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential

• Published in: ACS medicinal chemistry letters 2014-05, Vol.5 (5), p.480-484
• Main Authors: Gangjee, Aleem, Pavana, Roheeth Kumar, Ihnat, Michael A, Thorpe, Jessica E, Disch, Bryan C, Bastian, Anja, Bailey-Downs, Lora C, Hamel, Ernest, Bai, Rouli
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml4004793

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) inhibitors with antitubulin agents have been particularly successful. We have discovered a novel, potentially important analogue, that combines potent VEGFR2 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.