1. Aminothiazolones as potent, selective and cell active inhibitors of the PIM kinase family
- Author
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Carole J. R. Bataille, Alan M. Jones, Simon Byrne, Abigail R R Guillermo, Graham Michael Wynne, Angela J. Russell, J.M. Elkins, Isabel V.L. Wilkinson, Stefan Knapp, Camilo E. Quevedo, Matthew J. Durbin, Roderick G. Walker, Stephen G. Davies, and Anna Nadali more...
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,PIM1 ,01 natural sciences ,Biochemistry ,Serine ,Structure-Activity Relationship ,Proto-Oncogene Proteins c-pim-1 ,hemic and lymphatic diseases ,Drug Discovery ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Molecular Biology ,ADME ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Chemistry ,Organic Chemistry ,0104 chemical sciences ,Thiazoles ,010404 medicinal & biomolecular chemistry ,Molecular Medicine ,Phosphorylation ,Efflux ,Intracellular - 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. more...
- Published
- 2020
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