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Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
- Source :
- Journal of medicinal chemistry. 60(6)
- Publication Year :
- 2017
-
Abstract
- Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
- Subjects :
- 0301 basic medicine
Male
Models, Molecular
Pyruvate dehydrogenase lipoamide kinase isozyme 1
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase phosphatase
Protein Serine-Threonine Kinases
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Adenosine Triphosphate
Cell Line, Tumor
Drug Discovery
Transferase
Humans
Protein Isoforms
HSP90 Heat-Shock Proteins
Phosphorylation
Protein Kinase Inhibitors
chemistry.chemical_classification
Prostatic Neoplasms
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Hit to lead
Molecular biology
030104 developmental biology
Enzyme
chemistry
Biochemistry
030220 oncology & carcinogenesis
Drug Design
Molecular Medicine
Adenosine triphosphate
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 60
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....eb5f231f5660155f00b4666296b0e799