title: Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential.
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.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Roheeth Kumar
authors.initials: RK
authors.lastname: Pavana
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy , Oklahoma City, Oklahoma 73117, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy , Oklahoma City, Oklahoma 73117, United States.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Thorpe
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Disch
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy , Oklahoma City, Oklahoma 73117, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Bastian
authors.affiliation: Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy , Oklahoma City, Oklahoma 73117, United States.
authors.forename: Lora C
authors.initials: LC
authors.lastname: Bailey-Downs
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Rouli
authors.initials: R
authors.lastname: Bai
keywords: Antitubulin; VEGFR2 inhibition; antiangiogenic; antimitotic; combination chemotherapy