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

Jonathan B. Steinman, Cristina C. Santarossa, Rand M. Miller, Lola S. Yu, Anna S. Serpinskaya, Hideki Furukawa, Sachie Morimoto, Yuta Tanaka, Mitsuyosh Nishitan, Moriteru Asano, Ruta Zalyte, Alison E. Ondrus, Alex G. Johnson, Fan Ye, Maxence V. Nachury, Yoshiyuki Fukase, Kazuyoshi Aso, Michael A. Foley, Vladimir I. Gelfand, James K. ChenAndrew P. Carter, Tarun M. Kapoor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Article numbere25174
JournaleLife
Volume6
DOIs
StatePublished - May 19 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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