全景望远镜
全血
蛋白质组
体内
威罗菲尼
组蛋白脱乙酰酶抑制剂
化学
癌症研究
组蛋白脱乙酰基酶
组蛋白
生物
生物化学
DNA
黑色素瘤
免疫学
生物技术
转移性黑色素瘤
作者
Jessica Perrin,Thilo Werner,Nils Kurzawa,Anna Rutkowska,Dorothee Childs,Mathias Kalxdorf,Daniel Poeckel,Eugenia Stonehouse,Katrin Strohmer,Bianca Heller,Douglas W. Thomson,Jana Krause,Isabelle Becher,H. Christian Eberl,Johanna Vappiani,Daniel C. Sévin,Christina Rau,Holger Franken,Wolfgang Huber,Maria Faelth-Savitski,Mikhail M. Savitski,Marcus Bantscheff,Giovanna Bergamini
标识
DOI:10.1038/s41587-019-0388-4
摘要
Monitoring drug-target interactions with methods such as the cellular thermal-shift assay (CETSA) is well established for simple cell systems but remains challenging in vivo. Here we introduce tissue thermal proteome profiling (tissue-TPP), which measures binding of small-molecule drugs to proteins in tissue samples from drug-treated animals by detecting changes in protein thermal stability using quantitative mass spectrometry. We report organ-specific, proteome-wide thermal stability maps and derive target profiles of the non-covalent histone deacetylase inhibitor panobinostat in rat liver, lung, kidney and spleen and of the B-Raf inhibitor vemurafenib in mouse testis. In addition, we devised blood-CETSA and blood-TPP and applied it to measure target and off-target engagement of panobinostat and the BET family inhibitor JQ1 directly in whole blood. Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.
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