Article

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: 42.35). 06/2012; 486(7401):80-4. DOI: 10.1038/nature11127
Source: PubMed

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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    • "With the development of quantifiable high-throughput screening methodology at the larval-pupal stage (Gladstone and Su, 2011; Willoughby et al., 2013) or adult stage (Markstein et al., 2014), the Drosophila model is highly amenable for anti-cancer drug discovery. Whilst in its early days, Drosophila shows great promise in revealing novel drugs that can be taken into the clinic, which is best highlighted by drugs targeting Ret-driven MEN2 thyroid tumours (Dar et al., 2012; Das and Cagan, 2010, 2013; Read et al., 2005; Vidal et al., 2005). At present, only a few tumour models have been utilised for identification of anti-cancer compounds (Ret-driven MEN2 thyroid tumours, Raf-induced colorectal tumours, Ras V12 polarity impaired epithelial tumours and P53 or chk1-driven tumours). "
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    • "Recently, promising clinical effects of RET targeting therapy using cabozantinib [24] and vandetanib [25] were reported. A study using a Drosophila screening system suggested that the antitumor activity and toxicity of RET inhibitors were modified by the ''off-target'' kinase inhibition profiles [26]. Because, lenvatinib, cabozantinib and vandetanib have different kinase inhibitory profiles [27], further investigation to elucidate how these differences in kinase inhibitory profiles affect the antitumor activity and toxicity is anticipated. "
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    • "Network biology theory predicts that compared to exquisitely selective compounds for a single target, a promiscuous drug or a drug combination that simultaneously modulates multiple proteins in one process or parallel processes can be more efficacious for the treatment of complex disease (Boran & Iyengar, 2010; Kamb, Wee, & Lengauer, 2007; Keith et al., 2005; Schadt, Friend, & Shaywitz, 2009). Recently, Dar, Das, Shokat, and Cagan (2012) "
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