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Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family. 2020
Camilo E Quevedo, and
Carole J R Bataille, and
Simon Byrne, and
Matthew Durbin, and
Jon Elkins, and
Abigail Guillermo, and
Alan M Jones, and
Stefan Knapp, and
Anna Nadali, and
Roderick G Walker, and
Isabel V L Wilkinson, and
Graham M Wynne, and
Stephen G Davies, and
Angela J Russell
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
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.
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Angela J Russell
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Angela J Russell
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