Molecular cancer therapeutics, 2017-06, Vol.16 (6), p.1054-1067
2017
Details
- Autor(en) / Beteiligte
- Titel
- Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics
- Ist Teil von
- Molecular cancer therapeutics, 2017-06, Vol.16 (6), p.1054-1067
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-7163eISSN: 1538-8514DOI: 10.1158/1535-7163.MCT-16-0568-TTitel-ID: cdi_osti_scitechconnect_1374623
- Format
- –
- Schlagworte
- Animals, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Biotechnology, Blood, Cancer, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Survival - drug effects, Cells (biology), Drug Design, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor - methods, Drug Synergism, Hematologic Neoplasms - drug therapy, Hematologic Neoplasms - metabolism, Hematologic Neoplasms - pathology, Hematopoietic stem cells, Hematopoietic Stem Cells - drug effects, Hematopoietic Stem Cells - metabolism, Humans, Inhibition, Inhibitors, Janus kinase 2, Janus Kinase 2 - antagonists & inhibitors, Janus Kinase 2 - metabolism, Kinases, Lead compounds, Mice, Models, Molecular, Molecular Conformation, Neoplasia, Probes, Progenitor cells, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Proteins - antagonists & inhibitors, Proteins - chemistry, Sensitivity analysis, Structure-Activity Relationship, Synergism, Tumor cell lines, Tyrosine, Xenograft Model Antitumor Assays