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Citation
Dar, A.C., Das, T.K., Shokat, K.M., Cagan, R.L. (2012). Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.  Nature 486(7401): 80--84.
FlyBase ID
FBrf0218587
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC3703503 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nature
    Title
    Nature
    Publication Year
    1869-
    ISBN/ISSN
    0028-0836
    Data From Reference
    Alleles (6)
    Genes (5)
    Human Disease Models (1)
    Insertions (2)
    Transgenic Constructs (1)