Article | Published:

Chemical genetic discovery of targets and anti-targets for cancer polypharmacology

Nature volume 486, pages 8084 (07 June 2012) | Download Citation

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.

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Acknowledgements

We thank the Bloomington Stock Center, Vienna Drosophila RNAi Center and C. Pfleger for reagents. T.K.D. and R.C. were supported by National Institutes of Health grants R01CA109730 and R01CA084309 and American Cancer Society Grant 120616-RSGM-11-018-01-CDD. T.K.D. was also supported by American Cancer Society Grant 120886-PFM-11-137-01-DDC. We thank members of the Shokat and Cagan laboratories for discussions. We thank members of the SelectScreen team at Invitrogen, in particular K. Vogel, for performing kinase-profiling services. K.M.S. thanks NIH R01EB001987, P01 CA081403-11 and The Waxman Foundation.

Author information

Author notes

    • Arvin C. Dar
    •  & Tirtha K. Das

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA

    • Arvin C. Dar
    •  & Kevan M. Shokat
  2. Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Tirtha K. Das
    •  & Ross L. Cagan

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Contributions

A.C.D. and T.K.D. contributed equally and are listed alphabetically. A.C.D. and T.K.D. conceived and designed experiments with K.M.S. and R.C. A.C.D. performed chemical synthesis, modelling, IC50 measurements, informatics and western blots on cancer cell lines. T.K.D. performed, imaged and analysed all Drosophila assays and cancer cell line viability assays. All authors discussed experimental data and wrote the manuscript.

Competing interests

The authors are inventors on a joint University of California San Francisco and Mount Sinai patent application.

Corresponding author

Correspondence to Kevan M. Shokat.

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    Supplementary Information

    This file contains Supplementary Tables 1-4, Supplementary Figures 1-9 and Supplementary Methods.

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DOI

https://doi.org/10.1038/nature11127

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