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Elife. 2017 May 19;6. pii: e25174. doi: 10.7554/eLife.25174.

Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action.

Author information

1
Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, United States.
2
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
3
Tri-Institutitional Therapeutics Discovery Institute, New York, United States.
4
Pharmaceutical Research Division, Takeda Pharmaceuticals Ltd, Kanagawa, Japan.
5
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
6
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, United States.
7
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, United States.
8
Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States.

Abstract

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition.

KEYWORDS:

Hedgehog pathway; biochemistry; chemical biology; human

PMID:
28524820
PMCID:
PMC5478271
DOI:
10.7554/eLife.25174
[Indexed for MEDLINE]
Free PMC Article

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