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Cell Chem Biol. 2018 Apr 19;25(4):357-369.e6. doi: 10.1016/j.chembiol.2017.12.014. Epub 2018 Jan 27.

Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein.

Author information

1
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany; Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
2
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
3
Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
4
Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, North Rhine-Westphalia 44202, Germany.
5
Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, North Rhine-Westphalia 44202, Germany; Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Strasse 6, Dortmund, North Rhine-Westphalia 44227, Germany.
6
Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany.
7
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany; Technische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden, Dresden, Saxony 01307, Germany.
8
Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32827, USA.
9
Technische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden, Dresden, Saxony 01307, Germany.
10
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: schroer@jhu.edu.
11
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany; Medical Faculty, University of Münster, Domagkstrasse 3, Münster, North Rhine-Westphalia 48149, Germany. Electronic address: h.schoeler@mpi-muenster.mpg.de.
12
Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, North Rhine-Westphalia 44202, Germany; Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany. Electronic address: herbert.waldmann@mpi-dortmund.mpg.de.
13
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany; Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany. Electronic address: jared.sterneckert@tu-dresden.de.

Abstract

Aberrant hedgehog (Hh) signaling contributes to the pathogenesis of multiple cancers. Available inhibitors target Smoothened (Smo), which can acquire mutations causing drug resistance. Thus, compounds that inhibit Hh signaling downstream of Smo are urgently needed. We identified dynarrestin, a novel inhibitor of cytoplasmic dyneins 1 and 2. Dynarrestin acts reversibly to inhibit cytoplasmic dynein 1-dependent microtubule binding and motility in vitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay. Dynarrestin reversibly inhibits cytoplasmic dynein 2-dependent intraflagellar transport (IFT) of the cargo IFT88 and flux of Smo within cilia without interfering with ciliogenesis and suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. As such, dynarrestin is a valuable tool for probing cytoplasmic dynein-dependent cellular processes and a promising compound for medicinal chemistry programs aimed at development of anti-cancer drugs.

KEYWORDS:

ciliary transport; ciliobrevin; dynein; glioblastoma; hedgehog; intraflagellar transport; phenotypic screening; stem cell-based phenotypic screening; vismodegib

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