期刊
CELL CHEMICAL BIOLOGY
卷 25, 期 2, 页码 206-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2017.10.010
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资金
- AbbVie
- Bayer Pharma
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD) [115766]
- Janssen
- Merck
- MSD
- Novartis Pharma
- Ontario Ministry of Research, Innovation and Science (MRIS)
- Pfizer
- Sao Paulo Research Foundation - FAPESP
- Takeda
- Wellcome Trust [106169/ZZ14/Z]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U24DK116204] Funding Source: NIH RePORTER
For kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism. Although a number of acellular techniques have been developed to measure kinase binding or enzymatic inhibition, such approaches can fail to accurately predict engagement in cells. Here we report the application of an energy transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells. Using this method, we performed a selectivity profiling for clinically relevant kinase inhibitors against 178 full-length kinases, and a mechanistic interrogation of the potency offsets observed between cellular and biochemical analysis. For the multikinase inhibitor crizotinib, our approach accurately predicted cellular potency and revealed improved target selectivity compared with biochemical measurements. Due to cellular ATP, a number of putative crizotinib targets are unexpectedly disengaged in live cells at a clinically relevant drug dose.
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