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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 IC50 of 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.

We have recently introduced the term “stemistry” to describe the search for low molecular weight compounds, which are able to selectively modulate the behavior of resident stem and stemlike or progenitor cells within the tissues in which they exist. Such behavior includes manipulating their proliferation and differentiation to particular, new, cell types. It is envisaged that such agents would represent a totally new approach to the treatment of long-term degenerative disorders including cardiovascular disease, neurological disorders, diabetes, and macular degeneration. Existing treatments for these conditions are inadequate at best and involve significant levels of patient suffering and considerable costs to health systems throughout the world. This article reviews the evidence that this approach is feasible and indicates that the skills of medicinal chemists could make very significant contributions to the discovery and development of these agents.