Ung, P.M.U., Sonoshita, M., Scopton, A.P., Dar, A.C., Cagan, R.L., Schlessinger, A. (2019). Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network.  PLoS Comput. Biol. 15(4): e1006878.

FBrf0242306

Research paper

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.

PMC6506148 (PMC) (EuropePMC)