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

Masahiro Sonoshita; Alex P Scopton; Peter M U Ung; Matthew A Murray; Lisa Silber; Andres Y Maldonado; Alexander Real; Avner Schlessinger; Ross L Cagan; Arvin C Dar

doi:10.1038/nchembio.2556

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

Nat Chem Biol. 2018 Mar;14(3):291-298. doi: 10.1038/nchembio.2556. Epub 2018 Jan 22.

Authors

Affiliations

¹ Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Department of Systems Neuropharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
³ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Department of Biomedical Sciences, Florida State University, Tallahassee, Florida, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Carcinoma / metabolism*
Carcinoma, Neuroendocrine / metabolism*
Cell Line, Tumor
Cell Movement
Disease Models, Animal
Drosophila / metabolism*
Drug Design
Female
HCT116 Cells
Humans
Male
Mice
Mice, Inbred ICR
Molecular Docking Simulation
Neoplasm Transplantation
Protein Isoforms
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-raf / metabolism
Signal Transduction
Sorafenib / pharmacology
Thyroid Neoplasms / metabolism*

Substances

Protein Isoforms
Protein Kinase Inhibitors
Sorafenib
Proto-Oncogene Proteins c-raf
Raf1 protein, human

Supplementary concepts

Thyroid cancer, medullary

Associated data