Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network [article]

Peter Man-Un Ung, Masahiro Sonoshita, Alex P Scopton, Arvin C Dar, Ross L Cagan, Avner Schlessinger
2018 bioRxiv   pre-print
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) with disease-promoting
more » ... nase network activated by mutant dRet M955T . Structural models for kinases relevant to MTC were generated for virtually screening to identify initial hits that were dissimilar to known kinase inhibitors yet suppressed dRet M955T -induced oncogenicity. We then combined features from the hits and known inhibitors to create a hybrid molecule with improved dRet M955T phenotypic outcome. Our platform provides a framework to efficiently explore novel chemical spaces, develop compounds outside of the current inhibitor chemical space, and "correct" cancer-causing signaling networks to improve disease prognosis while minimizing whole body toxicity.
doi:10.1101/344192 fatcat:ltcrro7jsjcf5j726e7goqoqqq