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

Cytoplasmic Dynein Antagonists with Improved Potency and Isoform Selectivity.

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Laboratory of Chemistry and Cell Biology, Rockefeller University , New York City, New York 10065, United States.
Medical Research Council Laboratory of Molecular Biology , Division of Structural Studies, Cambridge CB2 0QH, United Kingdom.


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.

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