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Bioorg Med Chem. 2017 May 1;25(9):2657-2665. doi: 10.1016/j.bmc.2017.02.056. Epub 2017 Feb 28.

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

Author information

1
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
2
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK. Electronic address: steve.davies@chem.ox.ac.uk.
3
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK.
4
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
5
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Electronic address: angela.russell@chem.ox.ac.uk.

Abstract

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.

KEYWORDS:

Anti-cancer; High throughput screen; Kinase inhibitor; PIM kinase; Thiazolidine

PMID:
28341403
DOI:
10.1016/j.bmc.2017.02.056
[Indexed for MEDLINE]

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