期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 3, 页码 291-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2556
关键词
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资金
- Kyoto University Young Scholars Overseas Visit Program
- NIH [U54OD020353, R01-CA170495, R01-CA109730, R01-GM108911, DP2 CA186570-01]
- DOD [W81XWH-15-1-0111]
- Department of Defense [W81XWH-15-1-0539]
- Damon Runyon-Rachleff Foundation
- Scientific Computing at the Icahn School of Medicine at Mount Sinai
- NCI [P30 CA196521]
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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