The mitotic kinesin Eg5 overcomes inhibition to the phase I/II clinical candidate SB743921 by an allosteric resistance mechanism

Sandeep K. Talapatra, Nahoum Guillaume Hsuan Anthony, Simon MacKay, Frank Kozielski

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Development of drug resistance during cancer chemotherapy is one of the major causes of chemotherapeutic failure for the majority of clinical agents. The aim of this study was to investigate the underlying molecular mechanism of resistance developed by the mitotic kinesin Eg5 against the potent second-generation ispinesib analogue SB743921 (1), a phase I/II clinical candidate. Biochemical and biophysical data demonstrate that point mutations in the inhibitor-binding pocket decrease the efficacy of 1 by several 1000-fold. Surprisingly, the structures of wild type and mutant Eg5 in complex with 1 display no apparent structural changes in the binding configuration of the drug candidate. Furthermore, ITC and modelling approaches reveal that resistance to 1 is not through conventional steric effects at the binding site, but through reduced flexibility and changes in energy fluctuation pathways through the protein that influence its function. This is a phenomenon we have called 'resistance by allostery'.

Original languageEnglish
Pages (from-to)6317-6329
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number16
Early online date22 Jul 2013
Publication statusPublished - 22 Aug 2013


  • drug resistance
  • cancer chemotherapy
  • chemotherapeutic failure
  • molecular mechanism of resistance
  • mitotic kinesin Eg5
  • second-generation ispinesib analogue SB743921
  • phase I/II clinical candidate
  • allosteric resistance mechanism

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