Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity

ACS Chem Biol. 2016 Jan 15;11(1):53-60. doi: 10.1021/acschembio.5b00895. Epub 2015 Nov 11.


Cytoplasmic dyneins 1 and 2 are related members of the AAA+ superfamily (ATPases associated with diverse cellular activities) that function as the predominant minus-end-directed microtubule motors in eukaryotic cells. Dynein 1 controls mitotic spindle assembly, organelle movement, axonal transport, and other cytosolic, microtubule-guided processes, whereas dynein 2 mediates retrograde trafficking within motile and primary cilia. Small-molecule inhibitors are important tools for investigating motor protein-dependent mechanisms, and ciliobrevins were recently discovered as the first dynein-specific chemical antagonists. Here, we demonstrate that ciliobrevins directly target the heavy chains of both dynein isoforms and explore the structure-activity landscape of these inhibitors in vitro and in cells. In addition to identifying chemical motifs that are essential for dynein blockade, we have discovered analogs with increased potency and dynein 2 selectivity. These antagonists effectively disrupt Hedgehog signaling, intraflagellar transport, and ciliogenesis, making them useful probes of these and other cytoplasmic dynein 2-dependent cellular processes.

Publication types

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

MeSH terms

  • Animals
  • Cytoplasmic Dyneins / antagonists & inhibitors*
  • Cytoplasmic Dyneins / chemistry*
  • Hedgehog Proteins / physiology
  • Mice
  • Molecular Structure
  • NIH 3T3 Cells
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / chemistry
  • Quinazolinones / chemistry
  • Quinazolinones / pharmacology
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Substrate Specificity


  • Hedgehog Proteins
  • Protein Isoforms
  • Quinazolinones
  • Cytoplasmic Dyneins