Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
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.
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA.
Arvin C
AC
Dar
Tirtha K
TK
Das
Kevan M
KM
Shokat
Ross L
RL
Cagan
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D018814:Multiple Endocrine Neoplasia Type 2b / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019338:Polypharmacy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
C574118:AD57 compound; C574119:AD80 compound; C574120:AD81 compound; D001557:Benzenesulfonates; D029721:Drosophila Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C080148:tor protein, Drosophila; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases