Synthetic tailoring of approved drugs for new indications is often difficult, as the most appropriate targets may not be readily apparent, and therefore few roadmaps exist to guide chemistry. Here, we report a multidisciplinary approach for accessing novel target and chemical space starting from an FDA-approved kinase inhibitor. By combining chemical and genetic modifier screening with computational modeling, we identify distinct kinases that strongly enhance ('pro-targets') or limit ('anti-targets') whole-animal activity of the clinical kinase inhibitor sorafenib in a Drosophila medullary thyroid carcinoma (MTC) model. We demonstrate that RAF—the original intended sorafenib target—and MKNK kinases function as pharmacological liabilities because of inhibitor-induced transactivation and negative feedback, respectively. Through progressive synthetic refinement, we report a new class of 'tumor calibrated inhibitors' with unique polypharmacology and strongly improved therapeutic index in fly and human MTC xenograft models. This platform provides a rational approach to creating new high-efficacy and low-toxicity drugs.
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We thank K. Shokat, B. DeVita, and M. Birtwistle for critical comments on the manuscript. We thank members of the Cagan, Dar, and Schlessinger laboratories for important discussions. We thank P. Smibert (New York Genome Center) for ptc>dRetM955T flies, and K. Cook (Bloomington Drosophila Stock Center) for kinome mutant fly lines.M.S. was supported by The Kyoto University Young Scholars Overseas Visit Program. M.S. and R.L.C. were supported by NIH grants U54OD020353, R01-CA170495, and R01-CA109730 and DOD grant W81XWH-15-1-0111. P.M.U.U. and A.S. were supported by NIH grant R01-GM108911, and also by Department of Defense grant W81XWH-15-1-0539 (A.S.). The Dar laboratory is supported by Innovation awards from the NIH (DP2 CA186570-01) and Damon Runyon-Rachleff Foundation. A.C.D. is a Pew-Stewart Scholar in Cancer Research and Young Investigator of the Pershing-Square Sohn Cancer Research Alliance. We thank OpenEye Scientific Software, Inc. for granting us access to its high-performance molecular modeling applications through its academic license program. This work was also supported by Scientific Computing at the Icahn School of Medicine at Mount Sinai and NCI grant P30 CA196521 to the Tisch Cancer Institute. The data and reagents that support the findings of this study, including fly lines, homology models, and compounds, are available from the corresponding authors upon request.
M.S., A.P.S., R.L.C., and A.C.D. are inventors on a patent application submitted by the Icahn School of Medicine at Mount Sinai.
Supplementary Tables 1–5, Supplementary Figures 1–11 (PDF 5470 kb)
Reporting Summary (PDF 129 kb)
In vitro inhibition of kinases by APS6-45 (10). (XLSX 53 kb)
Numbers of samples (XLSX 45 kb)
Synthetic procedures (PDF 9341 kb)
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Sonoshita, M., Scopton, A., Ung, P. et al. A whole-animal platform to advance a clinical kinase inhibitor into new disease space. Nat Chem Biol 14, 291–298 (2018). https://doi.org/10.1038/nchembio.2556
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