Abstract |
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.
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Authors | Aleem Gangjee, Roheeth Kumar Pavana, Michael A Ihnat, Jessica E Thorpe, Bryan C Disch, Anja Bastian, Lora C Bailey-Downs, Ernest Hamel, Rouli Bai |
Journal | ACS medicinal chemistry letters
(ACS Med Chem Lett)
Vol. 5
Issue 5
Pg. 480-4
(May 08 2014)
ISSN: 1948-5875 [Print] United States |
PMID | 24900865
(Publication Type: Journal Article)
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