Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family.
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.
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Carole J R
CJ
Bataille
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Méabh B
MB
Brennan
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Simon
S
Byrne
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK. Electronic address: steve.davies@chem.ox.ac.uk.
Stephen G
SG
Davies
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Matthew
M
Durbin
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK.
Oleg
O
Fedorov
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Kilian V M
KV
Huber
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Alan M
AM
Jones
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK.
Stefan
S
Knapp
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Gu
G
Liu
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Anna
A
Nadali
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Camilo E
CE
Quevedo
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.
Angela J
AJ
Russell
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Roderick G
RG
Walker
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Robert
R
Westwood
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK.
Graham M
GM
Wynne
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D020014:K562 Cells; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D053778:Thiazolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
C000625360:5-((2-(3-N,N-dimethylsulfamoylamino)thiazol-4-yl)methylene)-2-thioxothiazolidin-4-one; D000970:Antineoplastic Agents; D007527:Isoenzymes; C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D053778:Thiazolidines; D012236:Rhodanine; C496634:PIM1 protein, human; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1
Anti-cancer; High throughput screen; Kinase inhibitor; PIM kinase; Thiazolidine