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Discovery and optimization of 4,5-diarylisoxazoles as potent dual inhibitors of pyruvate dehydrogenase kinase and heat shock protein 90.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Dec 11; Vol. 57 (23), pp. 9832-43. Date of Electronic Publication: 2014 Nov 26. - Publication Year :
- 2014
-
Abstract
- Upregulation of pyruvate dehydrogenase kinase (PDHK) has been observed in a variety of cancers. Inhibition of PDHK offers an attractive opportunity for the development of novel cancer therapies. To obtain novel PDHK inhibitors, we took advantage of the homology of the ATP-binding pocket between Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazole based HSP90 inhibitor for structural design. Our efforts led to the identification of 5k that inhibited PDHK1 with an IC50 value of 17 nM, which, however, showed marginal cellular activity. Further structural optimization resulted in compound 11a with improved cellular activity which could effectively modulate the metabolic profile of cancer cells and lead to the inhibition of cancer cell proliferation, evidenced by the increased oxidative phosphorylation and decreased glycolysis and associated oxidative stress. Our results suggested 11a as an excellent lead compound and a favorable biological tool to further evaluate the therapeutic potential of PDHK and HSP90 dual inhibitors in the treatment of cancer.
- Subjects :
- Antineoplastic Agents pharmacology
Cell Line, Tumor
Cell Proliferation drug effects
HSP90 Heat-Shock Proteins antagonists & inhibitors
Humans
Isoxazoles pharmacology
Piperazines pharmacology
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Structure-Activity Relationship
Antineoplastic Agents chemical synthesis
Isoxazoles chemical synthesis
Piperazines chemical synthesis
Protein Serine-Threonine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25383915
- Full Text :
- https://doi.org/10.1021/jm5010144