Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Carole J.R. Bataille, Méabh B. Brennan, Simon Byrne, Stephen G. Davies, Matthew Durbin, Oleg Fedorov, Kilian V.M. Huber, Alan M. Jones, Stefan Knapp, Gu Liu, Anna Nadali, Camilo E. Quevedo, Angela J. Russell, Roderick G. Walker, Robert Westwood, Graham M. Wynne
The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain haematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modelling and optimisation studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimised examples show good selectivity over other kinases. Two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 µM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition

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