A whole-animal platform to advance a clinical kinase inhibitor into new disease space

• Published in: Nature chemical biology Vol. 14; no. 3; pp. 291 - 298
• Main Authors: Sonoshita, Masahiro, Scopton, Alex P, Ung, Peter M U, Murray, Matthew A, Silber, Lisa, Maldonado, Andres Y, Real, Alexander, Schlessinger, Avner, Cagan, Ross L, Dar, Arvin C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2018; Nature Publishing Group
• Subjects: 49; 49/98; 631/67; 631/92/275; 631/92/436; 631/92/93; 64/24; 82; 82/1; 96/95; Animals; Animals, Genetically Modified; Binding sites; Biochemical Engineering; Biochemistry; Biology; Bioorganic Chemistry; Carcinoma - metabolism; Carcinoma, Neuroendocrine - metabolism; Cell Biology; Cell Line, Tumor; Cell Movement; Chemistry; Chemistry/Food Science; Computer applications; Disease Models, Animal; Drosophila - metabolism; Drug Design; Drugs; Enzyme inhibitors; FDA approval; Female; Fruit flies; Genetic screening; HCT116 Cells; Humans; Inhibitors; Insects; Kinases; Liabilities; Male; Medicine; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Negative feedback; Neoplasm Transplantation; Pharmacology; Protein Isoforms; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-raf - metabolism; Raf protein; Signal Transduction; Sorafenib - pharmacology; Thyroid; Thyroid cancer; Thyroid carcinoma; Thyroid Neoplasms - metabolism; Toxicity; Xenografts; Xenotransplantation
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2556

Combining
Drosophila
genetics with chemistry and computation led to the development of novel kinase inhibitors based on the RAF-targeting drug sorafenib that reveal the RET oncogene as an enhancer of drug action and improve the therapeutic window in medullary thyroid carcinoma models.
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.