Advantages of small-molecule inhibitors

by Professor Stephen Taylor

Small molecule inhibitors open up excellent opportunities to researchers studying multiple aspects of cell biology, ranging from cell cycle control and mitosis to signaling pathways and gene expression; and from migration and wound healing, to apoptosis and autophagy. Specifically, small molecule inhibitors offer several key advantages that are worth considering:

  • Small molecule inhibitors typically yield highly penetrant effects across whole cell populations. This facilitates, for example, large-scale biochemical experiments that are more difficult to achieve with RNAi where transfection and knock-down efficiencies can be limiting. 
  • In technical terms, using inhibitors is relatively straight forward, and they can easily be combined with other treatments, such as RNAi and other chemical-biology probes. 
  • Titration experiments using an inhibitor across a range of concentrations can reveal a spectrum of phenotypes, ranging from mild perturbation to near complete inhibition. 
  • Inhibitors can often inactivate their targets rapidly, allowing experiments to be done with precise temporal control. This is particularly important for studying regulators that act at various stages during the cell cycle, and thus small molecule inhibitors can facilitate “execution point” experiments.
  • In the case of enzymes such as protein kinases, inhibition with small molecules may still allow the enzyme to act as a scaffold for protein–protein interactions that would otherwise be disrupted by RNAi, thus allowing enzymatic and structural roles to be teased apart. 
  • If a small molecule is reversible, it may allow its target to first be inhibited then reactivated. 
  • And finally, small molecule approaches can easily be applied to different cell lines, even those from different species, including specialized cell types which may not amenable to RNAi-based strategies.


  • Weiss WA et al. Recognizing and exploiting differences between RNAi and small-molecule inhibitors. Nat Chem Biol, 3(12):739-44, 2007.

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