Discovery, Synthesis And Characterization Of Hexahydropyranoquinolines As A Novel Class Of Selective Inhibitors Of The Mitotic Kinesin Eg5.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5713 The concept of mitotic inhibition regained special attention after identification of the mitotic kinesin Eg5, which was validated as a drugable target using a chemical genetics approach. Eg5 inhibitors target a core component of dividing cells but may have an improved side effect profile in comparison to drugs interfering with tubulin dynamics. Here, we disclose a novel and promising class of Eg5 inhibitors. A broad lead optimization program of the hexahydropyranoquinoline (HHPQ) class, identified by an HTS campaign, revealed potent and selective inhibitors of the mitotic ATPase Eg5. Those Eg5 inhibitors specifically and reversibly dock into an allosteric binding pocket unique to Eg5, which is proven by X-ray crystallography and Biacore® binding studies. Proliferation in multiple cancer cell lines (e.g., Colo205, HCT116, SW707, MDA-MB468) is potently inhibited due to profound mitotic arrest with subsequent apoptosis. In vivo studies in mouse xenograft models using i.p. as well as oral administration showed excellent efficacy including response of the mitosis-specific biomarker phospho-histone H3 within tumor biopsies. In a rat model for peripheral neuropathy HHPQ-based Eg5 inhibitors are superior over taxane-based treatments. We conclude that our novel HHPQ Eg5 inhibitors have excellent potential as efficacious agents in the field of anti-cancer therapies.