Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family

Research output: Contribution to journalArticle

Authors

  • Camilo E. Quevedo
  • Carole J. R. Bataille
  • Simon Byrne
  • Matthew Durbin
  • Jon Elkins
  • Abigail Guillermo
  • Stefan Knapp
  • Anna Nadali
  • Roderick G. Walker
  • Isabel Wilkinson
  • Graham M. Wynne
  • Stephen G. Davies
  • Angela J. Russell

Colleges, School and Institutes

Abstract

We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner.

Details

Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Publication statusAccepted/In press - 26 Aug 2020