4.8 Article

An Unbiased Immunoaffinity-Based Strategy for Profiling Covalent Drug Targets In Vivo

期刊

ANALYTICAL CHEMISTRY
卷 91, 期 24, 页码 15818-15825

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.analchem.9b04118

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资金

  1. National Key R&D Program of China [2018YFC1312301, 2018YFC2000305]
  2. National Natural Science Foundation of China [81570060, 31870826]
  3. National Clinical Research Center for Geriatrics of West China Hospital at Sichuan University [Z20191001]

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Activity-based chemical proteomics approaches used for identifying cellular targets of drugs are mainly dependent on the availability of probes derived from drugs. However, all chemical probes are structurally different from the drugs themselves and cannot fully mimic the real actions of drugs in cells. Here we present a concise and unbiased immunoaffinity-based strategy for identifying covalent drug targets in vivo. By using the specific antibody, we not only confirm the well-known ibrutinib-binding target BTK, but also identify some previously undescribed strongly binding proteins, such as CKAP4 in human cell lines and TAP1 in mouse organs. The observed target profiles between species may partially explain why certain drug candidates are very effective in mice but not in humans. This approach avoids the chemical modification of drugs, eliminates the nonspecific bindings of chemical probes, and allows to unbiasedly decode the underlying mechanisms of action of covalent drugs.

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