A Whole Animal Platform to Advance A Clinical Kinase Inhibitor Into New Disease Space

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. 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 due to inhibitor-induced transactivation and negative feedback, respectively. Through progressive synthetic refinement, we report a novel 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 for creating new high efficacy/low toxicity drugs.