Dynarrestin, a Novel Inhibitor of Cytoplasmic Dynein

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 invitro without affecting ATP hydrolysis. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis byinducing spindle misorientation and pseudoprometaphase delay. Dynarrestin reversibly inhibitscytoplasmic dynein 2-dependent intraflagellar transport (IFT) of the cargo IFT88 and flux ofSmo within cilia without interfering with ciliogenesis and suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. Assuch, dynarrestin is a valuable tool for probing cytoplasmic dynein-dependent cellular processes and a promising compound for medicinal chemistryprograms aimed at development of anti-cancerdrugs.