1. Academic Validation
  2. The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5

The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5

  • Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. doi: 10.1016/j.bmcl.2010.01.110.
Kai Schiemann 1 Dirk Finsinger Frank Zenke Christiane Amendt Thorsten Knöchel David Bruge Hans-Peter Buchstaller Ulrich Emde Wolfgang Stähle Soheila Anzali
Affiliations

Affiliation

  • 1 MS-RTC-MedChem DA35, Merck Serono, Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany. kai.schiemann@merck.de
Abstract

Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and Apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15000
    99.55%, Kinesin抑制剂