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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    ABSTRACT: The vinegar fly, Drosophila melanogaster, has been a cornerstone of genetic analysis and cell and developmental biology research for over 100 years. Within the last decade, Drosophila is making its mark in translational research in its utilisation in modelling human diseases and in screens for small molecule inhibitors. In particular, its use in modelling cancer development and in identifying anti-cancer therapeutics is beginning to make an important contribution to the current drug discovery pipeline, which to date has been only poorly successful in delivering drugs, identified in vitro, into the clinic for anti-cancer therapy. The primary advantages of the Drosophila system for use in anti-cancer drug screening are the conservation of cancer genes/pathways between flies and mammals, its suitability for rapid phenotypic screening of chemicals for anti-cancer effects in vivo in a high-throughput and cost-effective manner and its use in identifying drugs that can specifically target tumours in vivo.
    Encyclopedia of Life Sciences, 03/2015; Wiley.
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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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    ABSTRACT: RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.
    Cancer letters 07/2013; 340(1). DOI:10.1016/j.canlet.2013.07.007 · 5.62 Impact Factor
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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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    ABSTRACT: Central to drug discovery and development is to comprehend the target(s), potency, efficacy and safety of drug molecules using pharmacological assays. The past decades have witnessed dramatic expansion of pharmacological assays ranging from molecular to phenotype assays, which is coincident with the realization of the innate complexity of drug-target interactions. The clinical features of a drug are defined by how it operates at the system level and by its distinct polypharmacology, ontarget, phenotypic and network pharmacology. Owing to their ability to provide a holistic view of drug actions in native cells, label-free biosensor-enabled cell phenotypic assays have been emerging as new generation phenotypic assays for drug discovery. Despite the benefits associated with wide pathway coverage, high sensitivity, high information content, non-invasiveness and real-time kinetics, label-free cell phenotypic assays are often viewed to be a blackbox in the era of target-centric drug discovery. I have therefore presented troubleshooting and deconvoluting approaches about how to relate label-free cell phenotypic signatures to the biochemical, cellular and molecular mechanisms of action of drugs.
    Journal of pharmacological and toxicological methods 01/2013; 67. DOI:10.1016/j.vascn.2013.01.004 · 2.15 Impact Factor
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