Kapoor Lab
  • Home
  • Research
    • Areas
    • Highlights
    • Technologies
  • Publications
    • Featured
    • Chronology
  • People
    • Current Members
    • Past Members
    • Lab Fun
  • Contact
Firestone, A.J., Weinger, J.S., Maldonado, M., Barlan, K., Langston, L.D., O'Donnell, M., Gelfand, V.I., Kapoor. T.M.*, Chen, J.K.* (2012) Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. Nature, 484, 125-9 [*corresponding authors] (Highlighted in Nature Reviews Drug Discovery, 11, 354; Nature Chemical Biology, 8, 503) 
                                   
Summary: Chemical inhibitors that allow protein function to be controlled on timescales of minutes to seconds can be powerful tools to analyze dynamic cellular processes. These chemical inhibitors can also provide starting points for developing drugs. Currently, there are several important protein families for which there are no cell-permeable chemical inhibitors available. Until recently, this was also the case for the AAA+ (ATPases associated with diverse cellular activities) family. Eukaryotes have 50-80 AAA+ proteins that use chemical energy for substrate remodeling or generating force. These ATPases play important roles in a diverse of cellular processes, including DNA replication, protein unfolding, and intracellular transport. Important members of the AAA+ family are dyneins, microtubule-based motor proteins required for cell division, ciliary trafficking and organelle transport. Examining dynein functions in these diverse dynamic processes has been difficult using conventional approaches. In this report we describe the discovery of ciliobrevins, dihydroquinazolinone-based small molecules that are the first selective inhibitors of cytoplasmic dynein. We show that ciliobrevin treatment disrupts protein trafficking within the primary cilium and leads to shorter and malformed cilia. Consistent with these effects, Hedgehog signaling is blocked by ciliobrevins. These compounds also inhibit proper mitotic spindle assembly and block organelle transport in cultured cells. Together, these observations suggest that ciliobrevins inhibit cellular processes known to depend on dynein function. Further, we show that ciliobrevins block dynein-dependent microtubule gliding and ATPase activity in vitro, but do not inhibit other microtubule-based motor proteins or other AAA+ proteins. Our data indicate that ciliobrevins will be powerful probes for unraveling dynein function in a wide range of biological contexts. Ciliobrevins will also provide starting points for developing new chemical probes for other AAA+ proteins and will facilitate the development of therapeutic agents targeting members of this protein superfamily.
Proudly powered by Weebly