We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network.
- Authors
Ung, Peter M. U.; Sonoshita, Masahiro; Scopton, Alex P.; Dar, Arvin C.; Cagan, Ross L.; Schlessinger, Avner
- Abstract
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.
- Subjects
DROSOPHILA; MEDULLARY thyroid carcinoma; ANIMAL models of cancer; KINASE inhibitors; ORGANIC synthesis; CHEMICAL libraries
- Publication
PLoS Computational Biology, 2019, Vol 15, Issue 4, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1006878