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

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

doi:10.1016/j.bmc.2017.02.056

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

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

Authors

Affiliations

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: [email protected].
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: [email protected].

PMID: 28341403
DOI: 10.1016/j.bmc.2017.02.056

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Humans
Isoenzymes / antagonists & inhibitors
K562 Cells
Mice
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
Rhodanine / analogs & derivatives*
Rhodanine / chemical synthesis
Rhodanine / pharmacokinetics
Rhodanine / pharmacology
Solubility
Sulfonamides / chemical synthesis
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*
Thiazolidines / chemical synthesis
Thiazolidines / pharmacokinetics
Thiazolidines / pharmacology*

Substances

5-((2-(3-N,N-dimethylsulfamoylamino)thiazol-4-yl)methylene)-2-thioxothiazolidin-4-one
Antineoplastic Agents
Isoenzymes
PIM2 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Sulfonamides
Thiazolidines
Rhodanine
PIM1 protein, human
PIM3 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-pim-1

Abstract

MeSH terms

Substances

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