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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Antiangiogenic agents (AA) are cytostatic and used in combination chemotherapy.
• Vascular endothelial growth factor receptor-2 (VEGFR2) inhibitors combined with antitubulin agents show clinical success.
• Tumor resistance mechanisms like P-glycoprotein and β-III tubulin expression limit antimicrotubule agent efficacy.

Purpose of the Study:

• To discover and characterize a novel single-molecule agent with combined VEGFR2 inhibitory and antitubulin activities.
• To evaluate the compound's efficacy against the NCI 60 tumor cell panel.
• To assess the compound's ability to overcome common drug resistance mechanisms and its in vivo antitumor activity and toxicity.

Main Methods:

• Synthesis of a novel dual-activity molecule.
• In vitro evaluation of VEGFR2 inhibition and tubulin assembly inhibition.
• Assessment of GI50 values across the NCI 60 tumor cell panel.
• Testing of resistance mechanism circumvention (P-glycoprotein and β-III tubulin expression).
• In vivo antitumor efficacy studies in comparison to standard chemotherapeutics.

Main Results:

• The novel analogue demonstrated potent VEGFR2 inhibition comparable to sunitinib and antitubulin activity comparable to combretastatin A-4.
• Achieved GI50 values of 10(-7) M across the NCI 60 tumor cell panel.
• Potently inhibited tubulin assembly and circumvented P-glycoprotein and β-III tubulin-mediated resistance.
• The HCl salt form was freely water-soluble.
• Exhibited superior in vivo antitumor activity compared to docetaxel, sunitinib, and temozolomide, with no observed toxicity.

Conclusions:

• A novel single-molecule agent with combined antiangiogenic and antitubulin properties has been discovered.
• This compound exhibits broad-spectrum anticancer activity, overcomes key resistance mechanisms, and shows promising in vivo efficacy without toxicity.
• This dual-action agent represents a potentially significant advancement in cancer chemotherapy.