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

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


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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Drug Resistance, Neoplasm
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*


  • Antineoplastic Agents