Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein,Cell Chemical Biology

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Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-01-30 , DOI: 10.1016/j.chembiol.2017.12.014
Susanne Höing ₁ , Ting-Yu Yeh ₂ , Matthias Baumann ₃ , Nancy E Martinez ₄ , Peter Habenberger ₃ , Lea Kremer ₅ , Hannes C A Drexler ₆ , Philipp Küchler ₄ , Peter Reinhardt ₇ , Axel Choidas ₃ , Mia-Lisa Zischinsky ₃ , Gunther Zischinsky ₃ , Swaran Nandini ₈ , Aaron P Ledray ₈ , Stephanie A Ketcham ₂ , Lydia Reinhardt ₇ , Masin Abo-Rady ₉ , Michael Glatza ₇ , Stephen J King ₈ , Peter Nussbaumer ₃ , Slava Ziegler ₄ , Bert Klebl ₃ , Trina A Schroer ₂ , Hans R Schöler ₁₀ , Herbert Waldmann ₁₁ , Jared Sterneckert ₁₂

Affiliation

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.
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, North Rhine-Westphalia 44202, Germany.
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.
Bioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster, North Rhine-Westphalia 48149, Germany.
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.
Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL 32827, USA.
Technische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden, Dresden, Saxony 01307, Germany.
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.
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.
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.

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 motilityin vitrowithout 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.

中文翻译：

Dynarrestin，一种新型的细胞质动力蛋白抑制剂

异常刺猬 (Hh) 信号传导有助于多种癌症的发病机制。可用的抑制剂靶向平滑 (Smo)，它可以获得导致耐药性的突变。因此，迫切需要抑制 Smo 下游 Hh 信号的化合物。我们鉴定了 dynarrestin，一种新型的细胞质动力蛋白 1 和 2 抑制剂。 Dynarrestin 可逆地抑制细胞质动力蛋白 1 依赖性微管结合和体外运动，而不影响 ATP 水解。它通过诱导纺锤体定向错误和假前中期延迟来快速且可逆地抑制活细胞中的内体运动并扰乱有丝分裂。Dynarrestin 可逆地抑制货物 IFT88 的细胞质动力蛋白 2 依赖性鞭毛内运输 (IFT) 和纤毛内 Smo 的通量，而不干扰纤毛发生，并抑制神经元前体和肿瘤细胞的 Hh 依赖性增殖。因此，dynarrestin 是探索细胞质动力蛋白依赖性细胞过程的宝贵工具，也是旨在开发抗癌药物的药物化学项目的有前途的化合物。

更新日期：2018-04-19

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