Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action
- Rockefeller University, United States
- Feinberg School of Medicine, Northwestern University, United States
- Tri-Institutitional Therapeutics Discovery Institute, United States
- Takeda Pharmaceuticals Ltd., Japan
- MRC Laboratory of Molecular Biology, United Kingdom
- California Institute of Technology, United States
- Stanford University, United States
- Stanford University School of Medicine, United States
- Northwestern University, United States
Abstract
Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that power transport of cellular cargos towards 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 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. We identified dynapyrazoles, inhibitors more potent than ciliobrevins in vitro, and find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles block only microtubule-stimulated activity. Single-digit micromolar concentrations of dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Together, our studies suggest that chemical structure-based analyses can lead to inhibitors with distinct modes of inhibition and improved properties.
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Author details
Funding
National Institutes of Health (R01 GM098579)
- Tarun M Kapoor
Robertson Therapeutic Development Fund
- Tarun M Kapoor
Damon Runyon Cancer Research Foundation (DRG-2222-15)
- Rand M Miller
Medical Research Council (MC_UP_A025_1011)
- Andrew P Carter
National Institutes of Health (T32GM007739)
- Jonathan Baruch Steinman
National Institutes of Health (R01 GM52111)
- Vladimir I Gelfand
National Institutes of Health (R01 GM113100)
- James K Chen
Wellcome (WT100387)
- Andrew P Carter
National Institutes of Health (R01 GM089933)
- Maxence V Nachury
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Steinman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action
eLife 6:e25174.
https://doi.org/10.7554/eLife.25174
