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

Journal article

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.

Authors: Bataille, C; Brennan, M; Byrne, S; Davies, S; Durbin, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Bioorganic & Medicinal Chemistry
• Volume: 25
• Issue: 9
• Pages: 2657-2665
• Publication date: 2017-02-01
• Acceptance date: 2017-02-25
• DOI: 10.1016/j.bmc.2017.02.056
• ISSN: 0968-0896 and 1464-3391
• Language: English
• Keywords: Anti-cancer; Thiazolidine; Kinase inhibitor; High throughput screen; PIM kinase