Discovery of Dual VEGFR-2 and Tubulin Inhibitors with in Vivo Efficacy

Abstract

In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…Many kinase inhibitors have also been shown to modulate MTs and affect their functions as well . These dual inhibitors, in many cases, through their multiple MOAs, have been observed to cause substantially enhanced apoptosis of cancer cells and strongly overcome cancer cell resistance compared with their single inhibitor counterparts . Additionally, numerous tubulin/kinase dual inhibitors have been observed to demonstrate substantially lower toxicities to normal cells with significantly higher maximum tolerated dose (MTD), overcoming one of the major limitations of single‐tubulin inhibitor–based therapeutic agents .…”

“…Additionally, numerous tubulin/kinase dual inhibitors have been observed to demonstrate substantially lower toxicities to normal cells with significantly higher maximum tolerated dose (MTD), overcoming one of the major limitations of single‐tubulin inhibitor–based therapeutic agents . In the event of dual inhibition, it is difficult to understand which MOA is responsible for the underlying cell toxicity and cell cycle arrest, given that both kinase and tubulin inhibitors are responsible for either phenotype . In recent years, cell cycle arrest analysis at G 0 /G 1 phase and at G 2 /M phase as well as image analysis of cellular phenotypes has provided insight into a drug candidate’s dual MOAs .…”

“…Chekler et al have developed dual inhibitors of vascular endothelial growth factor receptor 2 (VEGFR‐2) kinase and tubulin, capable of inhibiting both tumor growth and tumor vasculature with enhanced synergistic antitumor responses in animal studies than respective inhibitors alone. They started with the triazole lead enhancer of polycomb homolog 1 ( EPC‐1 ) ( 46 ; Figure ), weak VEGFR kinase inhibitor and obtained the oxadiazole EPC‐17 ( 47 ; Figure ) as the potent dual inhibitor of VEGFR‐2 as well as tubulin polymerization.…”

“…[141][142][143] These dual inhibitors, in many cases, through their multiple MOAs, have been observed to cause substantially enhanced apoptosis of cancer cells and strongly overcome cancer cell resistance compared with their single inhibitor counterparts. [143][144][145][146][147][148][149] Additionally, numerous tubulin/kinase dual inhibitors have been observed to demonstrate substantially lower toxicities to normal cells with significantly higher maximum tolerated dose (MTD), overcoming one of the major limitations of single-tubulin inhibitor-based therapeutic agents. 147,150,151 In the event of dual inhibition, it is difficult to understand which MOA is responsible for the underlying cell toxicity and cell cycle arrest, given that both kinase and tubulin inhibitors are responsible for either phenotype.…”

Design, Synthesis, and Biological Evaluation of (E)-N-Aryl-2-arylethenesulfonamide Analogues as Potent and Orally Bioavailable Microtubule-Targeted Anticancer Agents

“…Because of the clinical success of microtubule-affecting compounds such as paclitaxel, the vinca alkaloids, and epothilone derivatives in the treatment of a wide variety of cancers, it has been argued that microtubules represent the single most important protein target for anticancer therapy. 8 …”