Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network
Fig 6
Hybrid compounds with improved efficacy.
(A) The kinase inhibitors imatinib, sorafenib, and 2–3 share the common N-phenylcarboxamide moiety (grey box), while the 1H-indole-2-carboxamide of 2–3 resembles the urea linker of sorafenib (blue box). (B) Hybridization of 2 and sorafenib and AD-80 yielded 3 and 4, respectively. Top, chemical structures of compounds. Bottom, docking poses of compounds in a RET DFG-out model. (C) 3 rescued ptc>dRetM955T flies more effectively than by either 2 or sorafenib alone. (-), vehicle control. Error bars represent standard error in triplicate experiments. *P < 0.05 in one-sided Student’s t-test as compared with no-drug control. (D) 3 suppresses migration of dRetM955T-expressing wing disc cells from the original domain (green) similarly to the positive control, sorafenib. Top and bottom, apical and z-series views at the yellow dotted lines in apical view, respectively. Arrows, migrating cells. White scale bars, 50 μm.