Journal article
Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases
Journal of medicinal chemistry, Vol.52(1), pp.74-86
01/08/2009
Handle:
https://hdl.handle.net/2376/103414
PMCID: PMC5404933
PMID: 19072652
Abstract
The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (
4a
) was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells. Although
4a
is a competitive inhibitor with respect to ATP, a screen of approximately 50 diverse protein kinases demonstrated that it has high selectivity for Pim kinases. Computational docking of
4a
to Pim-1 provided a model for lead optimization, and a series of substituted thiazolidine-2,4-dione congeners was synthesized. The most potent new compounds exhibited IC
50
s of 13 nM for Pim-1 and 2.3 µM for Pim-2. Additional compounds in the series demonstrated selectivities of more than 2500-fold and 400-fold for Pim-1 or Pim-2, respectively, while other congeners were essentially equally potent toward the two isozymes. Overall, these compounds are new Pim kinase inhibitors that may provide leads to novel anticancer agents.
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Details
- Title
- Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases
- Creators
- Zuping Xia - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South CarolinaChristian Knaak - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South CarolinaJian Ma - Department of Medicine, Medical University of South CarolinaZanna M Beharry - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South CarolinaCampbell McInnes - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South CarolinaWenxue Wang - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South CarolinaAndrew S Kraft - Department of Medicine, Medical University of South CarolinaCharles D Smith - Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina
- Publication Details
- Journal of medicinal chemistry, Vol.52(1), pp.74-86
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Identifiers
- 99900546661101842
- Language
- English
- Resource Type
- Journal article