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Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
- Source :
- Journal of Medicinal Chemistry. 60:9184-9204
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.
- Subjects :
- Male
0301 basic medicine
Thermal shift assay
Antineoplastic Agents
Pyrazole
Crystallography, X-Ray
Article
Permeability
Mice
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Oxidoreductase
Cell Line, Tumor
Lactate dehydrogenase
Drug Discovery
Animals
Humans
Structure–activity relationship
Glycolysis
Enzyme Inhibitors
chemistry.chemical_classification
L-Lactate Dehydrogenase
Chemistry
Drug discovery
Membranes, Artificial
High-Throughput Screening Assays
Rats
Thiazoles
030104 developmental biology
Enzyme
Solubility
Biochemistry
Microsomes, Liver
Pyrazoles
Molecular Medicine
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....35ab4eead50d1c0b1059bfc4f4687a51