ArticleeLife2017
Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action.
Article in eLife, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Functional Specialization of Clathrin-Independent Endocytic Routes: Mechanisms and Cellular Roles.Traffic (Copenhagen, Denmark) · 2026Review
- The cell cycle variant in multiciliated cells incorporates 2 centriole biogenesis cycles.bioRxiv : the preprint server for biology · 2026Article
- Mitochondrial DNA mutations and intercellular mitochondrial transfer in cancer: mechanisms, biological effects, and clinical potential.Biomarker research · 2026Review
- Human MX1 orchestrates the cytoplasmic sequestration of neosynthesized influenza A virus vRNPs.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Application of temperature replica exchange molecular dynamics: Structure of mitotic spindle-associated protein SHE1 and its binding to dynein.Computational and structural biotechnology journal · 2025Article
- A Thermo-responsive collapse system for controlling heterogeneous cell localization, ratio and interaction for three-dimensional solid tumor modeling.bioRxiv : the preprint server for biology · 2024Article
- A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.The Journal of cell biology · 2024Article
- Temporal Patterns of Angular Displacement of Endosomes: Insights into Motor Protein Exchange Dynamics.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The physical and cellular mechanism of structural color change in zebrafish.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cargo specificity, regulation, and therapeutic potential of cytoplasmic dynein.Experimental & molecular medicine · 2024Review
- Dynein functions in galectin-3 mediated processes of clathrin-independent endocytosis.Journal of biosciences · 2024Article
- Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer.bioRxiv : the preprint server for biology · 2023Article
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- Targeting allostery in the Dynein motor domain with small molecule inhibitors.Cell chemical biology · 2021Article
- Rotavirus Viroplasm Biogenesis Involves Microtubule-Based Dynein Transport Mediated by an Interaction between NSP2 and Dynein Intermediate Chain.Journal of virology · 2021Article
- Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical "Toolkit".International journal of molecular sciences · 2021Article
- Biochemical reconstitutions reveal principles of human γ-TuRC assembly and function.The Journal of cell biology · 2021Article
- A High-Throughput Cellular Screening Assay for Small-Molecule Inhibitors and Activators of Cytoplasmic Dynein-1-Based Cargo Transport.SLAS discovery : advancing life sciences R & D · 2020Article
Corrections and comments
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Authors and funding
22 authors.
Funding
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.
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Registered trials
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