Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network.

PLoS Comput Biol 2019 04 26;15(4):e1006878. Epub 2019 Apr 26.

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.

Drosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) characterized by a transformation network activated by oncogenic dRetM955T. Structural models for kinases relevant to MTC were generated for virtual screening to identify unique preliminary hits that suppressed dRetM955T-induced transformation. We then combined features from our hits with those of known inhibitors to create a 'hybrid' molecule with improved suppression of dRetM955T transformation. Our platform provides a framework to efficiently explore novel kinase inhibitors outside of explored inhibitor chemical space that are effective in inhibiting cancer networks while minimizing whole body toxicity.

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http://dx.doi.org/10.1371/journal.pcbi.1006878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506148PMC
April 2019
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