Crenolanib‐Derived Probes Suitable for Cell‐ and Tissue‐Based Protein Profiling and Single‐Cell Imaging

• Published in: Chembiochem : a European journal of chemical biology Vol. 20; no. 14; pp. 1783 - 1788
• Main Authors: Chang, Yu, Zhu, Dongsheng, Guo, Haijun, Yin, Xingfeng, Ding, Ke, Li, Zhengqiu
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 15.07.2019; Wiley Subscription Services, Inc
• Subjects: Acute myeloid leukemia; Biochemistry & Molecular Biology; cancer; Chemistry, Medicinal; fluorescence; Fluorescent indicators; imaging agents; inhibitors; Leukemia; Life Sciences & Biomedicine; Medical imaging; Myeloid leukemia; Pharmacology & Pharmacy; Probes; Proteins; proteomics; Science & Technology; Side effects; Toxicity; inhibitors; proteomics; fluorescence; FLT3; cancer; imaging agents; TARGET IDENTIFICATION; KINASE INHIBITOR
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201900067

Crenolanib (CP‐868,596), a potent inhibitor of FLT3 and PDGFRα/β, is currently under phase III clinical investigation for the treatment of acute myeloid leukemia. However, the protein targets of Crenolanib in cancer cells remain obscure, which results in difficulties in understanding the mechanism of actions and side effects. To alleviate this issue, in this study, a photoaffinity probe and two fluorescent probes were created based on Crenolanib, followed by competitive protein profiling and bioimaging studies, with the aim of characterizing the cellular targets. A series of unknown protein hits, such as MAPK1, SHMT2, SLC25A11, and HIGD1A, were successfully identified by means of pull‐down/LC‐MS/MS; these might provide valuable clues for understanding drug action and potential toxicities. Moreover, the fluorescent probes are suitable for imaging drug distribution at the single‐cell level. Tracking devices: Crenolanib is a potent inhibitor of FLT3 and PDGFRα/β currently under phase III clinical investigation for the treatment of acute myeloid leukemia. Potential cellular targets of Crenolanib are identified by means of affinity‐based proteome profiling, and cell‐ and tissue‐based imaging are performed to track the locations of target proteins.