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Trends Pharmacol Sci. 2017 Dec;38(12):1100-1109. doi: 10.1016/j.tips.2017.09.003. Epub 2017 Oct 13.

Leveraging Chemotype-Specific Resistance for Drug Target Identification and Chemical Biology.

Author information

1
Laboratory of Chemistry and Cell Biology, The Rockefeller University, 1200 York Ave., New York, NY 10065, USA. Electronic address: Kapoor@rockefeller.edu.
2
Laboratory of Chemistry and Cell Biology, The Rockefeller University, 1200 York Ave., New York, NY 10065, USA.

Abstract

Identifying the direct physiological targets of drugs and chemical probes remains challenging. Here we describe how resistance can be used to achieve 'gold-standard' validation of a chemical inhibitor's direct target in human cells. This involves demonstrating that a silent mutation in the target that suppresses inhibitor activity in cell-based assays can also reduce inhibitor potency in biochemical assays. Further, phenotypes due to target inhibition can be identified as those observed in the inhibitor-sensitive cells, across a range of inhibitor concentrations, but not in genetically matched cells with a silent resistance-conferring mutation in the target. We propose that chemotype-specific resistance, which is generally considered to be a limitation of molecularly targeted agents, can be leveraged to deconvolve the mechanism of action of drugs and to properly use chemical probes.

KEYWORDS:

chemical biology; chemical probes; drug resistance; target identification

PMID:
29037508
PMCID:
PMC5708298
DOI:
10.1016/j.tips.2017.09.003
[Indexed for MEDLINE]
Free PMC Article

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