Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family.
Bataille CJR., Brennan MB., Byrne S., Davies SG., Durbin M., Fedorov O., Huber KVM., Jones AM., Knapp S., Liu G., Nadali A., Quevedo CE., Russell AJ., Walker RG., Westwood R., Wynne GM.
The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological 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 modeling and optimization 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 optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic 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 IC50of 0.75μM 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.