Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28619751
DOI
10.1158/1535-7163.mct-17-0018
PII: 1535-7163.MCT-17-0018
Knihovny.cz E-resources
- MeSH
- Apoptosis drug effects MeSH
- Biomarkers MeSH
- Cell Cycle drug effects MeSH
- Checkpoint Kinase 1 antagonists & inhibitors MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Dealkylation drug effects MeSH
- Protein Kinase Inhibitors chemical synthesis pharmacology MeSH
- Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Methylation MeSH
- Disease Models, Animal MeSH
- Molecular Structure MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Pyrazoles pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Biomarkers MeSH
- Checkpoint Kinase 1 MeSH
- Protein Kinase Inhibitors MeSH
- MK-8776 MeSH Browser
- Antineoplastic Agents MeSH
- Pyrazoles MeSH
- Pyrimidines MeSH
Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.
Cellular Imaging Core Facility CELLIM CEITEC Masaryk University Brno Czech Republic
Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Chemistry CZ Openscreen Faculty of Science Masaryk University Brno Czech Republic
Department of Cytokinetics Institute of Biophysics CAS Brno Czech Republic
Department of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic
Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic
National Centre for Biomolecular Research Masaryk University Brno Czech Republic
References provided by Crossref.org
