Sonoshita, Masahiro published the artcileA whole-animal platform to advance a clinical kinase inhibitor into new disease space, Quality Control of 32333-53-2, the publication is Nature Chemical Biology (2018), 14(3), 291-298, database is CAplus and MEDLINE.
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 chem. Here, we report a multidisciplinary approach for accessing novel target and chem. space starting from an FDA-approved kinase inhibitor. By combining chem. 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 clin. 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 pharmacol. liabilities because of inhibitor-induced transactivation and neg. feedback, resp. Through progressive synthetic refinement, we report a new class of ‘tumor calibrated inhibitors’ with unique polypharmacol. 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.
Nature Chemical Biology published new progress about 32333-53-2. 32333-53-2 belongs to chlorides-buliding-blocks, auxiliary class Trifluoromethyl,Fluoride,Chloride,Sulfonyl chlorides,Benzene, name is 4-Chloro-3-(trifluoromethyl)benzenesulfonyl Chloride, and the molecular formula is C8H10S, Quality Control of 32333-53-2.
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