Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network
Fig 4
(A) Rescue of ptc>dRetM955T fly lethality by 1 and 1–1. Both showed improved efficacy (synergy) when co-administrated with 200 μM sorafenib (soraf). (-), vehicle DMSO control. Error bars represent standard error in triplicate experiments. *P < 0.05 in one-sided Student’s t-test as compared with vehicle control. (B) Docking pose of 1 and its analogs 1–1 and 1–2 (salmon sticks) with a DFG-out model of RET (broken yellow lines indicate hydrogen bonds), and their inhibition of migration of the dRetM955T-expressing cells. Right, suppression of cell migration by 1 and 1–1. Controls are shown in (C). (C) In vivo cell migration assay in ptc>dRetM955T flies. Left, a developing whole wing disc containing GFP-labeled, dRetM955T-expressing cells constituting a stripe in the midline. The disc margin is visualized with DAPI (red pseudocolor). There are wild-type cells in black areas. Center, overgrowth of dRetM955T-expressing cells resulting in the thickening of the stripe in the apical view (top). Virtual z-series view of confocal images derived from the plane indicated by yellow dotted lines (bottom) shows dRetM955T-expressing cells migrating away from the original domain (arrows). Right, sorafenib suppressed the migration. White scale bars, 50 μm.