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Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
- Source :
-
Nature [Nature] 2012 Jun 06; Vol. 486 (7401), pp. 80-4. Date of Electronic Publication: 2012 Jun 06. - Publication Year :
- 2012
-
Abstract
- The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the 'anti-target' Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine neoplasia type 2 models. Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems pharmacology approach towards developing compounds with a maximal therapeutic index.
- Subjects :
- Animals
Benzenesulfonates pharmacology
Cell Transformation, Neoplastic drug effects
Cell Transformation, Neoplastic pathology
Disease Models, Animal
Drosophila Proteins antagonists & inhibitors
Drosophila Proteins genetics
Drosophila Proteins metabolism
Drosophila melanogaster drug effects
Drosophila melanogaster genetics
Drug Evaluation, Preclinical
Drug-Related Side Effects and Adverse Reactions
Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases metabolism
Heterocyclic Compounds, 4 or More Rings adverse effects
Heterocyclic Compounds, 4 or More Rings chemistry
Heterocyclic Compounds, 4 or More Rings pharmacology
Heterocyclic Compounds, 4 or More Rings therapeutic use
Humans
Male
Multiple Endocrine Neoplasia Type 2b enzymology
Niacinamide analogs & derivatives
Phenylurea Compounds
Protein Kinase Inhibitors adverse effects
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Proto-Oncogene Proteins c-ret genetics
Proto-Oncogene Proteins c-ret metabolism
Pyridines pharmacology
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Signal Transduction drug effects
Sorafenib
Survival Rate
Xenograft Model Antitumor Assays
src-Family Kinases antagonists & inhibitors
src-Family Kinases metabolism
Molecular Targeted Therapy
Multiple Endocrine Neoplasia Type 2b drug therapy
Multiple Endocrine Neoplasia Type 2b genetics
Polypharmacy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 486
- Issue :
- 7401
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 22678283
- Full Text :
- https://doi.org/10.1038/nature11127