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

Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA.
Nature (Impact Factor: 41.46). 06/2012; 486(7401):80-4. DOI: 10.1038/nature11127
Source: PubMed


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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    • "Furthermore, small molecules can interact with numerous other proteins ( " off-targets " ) and there is also no rational procedure for understanding how the target-interaction profiles ( " chemoproteomic profiles " ; see section 3.5 for more details) correlate with the phenotype (Fig. 2).[5] [6] However, since the beginning of this century, the advent of the genomic era has presented researchers with a myriad of high throughput (HT) biological data † (parts lists and their interaction networks), which can assist in the optimization of efficacy and ADMET profiles in the traditional ligand-and structure-based approaches. This data rich era has, on the other hand, presented us with challenges related to integrating and analyzing multi-platform and multidimensional datasets and translating them into viable hypotheses. "
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    • "For example, knowledge of the compounds' molecular interaction with the target protein using structural approaches, such as X-ray crystallography, can be particularly powerful in facilitating rational drug design. For example, the structure of AD57 bound to the c-Src protein enabled logical design of new molecules with greater binding affinity (Dar et al., 2008, 2012). New derivates can then be tested in the Drosophila cancer model in comparison to their parent compound to assess their potency in vivo. "
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    • "Lastly, Drosophila is emerging as a useful platform for cancer drug discovery: flies provide a high degree of conservation of cancer relevant pathways as well as appropriate sensitivity to compounds targeting these pathways (Bangi et al., 2011; Gonzalez, 2013). Compound screens in Drosophila using organismal lethality or other complex phenotypic read outs of cancer are revealing new anti-cancer agents with promising activity in mammalian models (Dar et al., 2012). With these tools, Drosophila can be useful both as a genetic model system for tumor immunology but also as a drug discovery platform to screen for compounds that target the immune system and its interactions with tumor cells. "
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