Small-Molecule Inhibitors Of The AAA+ Atpase Motor Cytoplasmic Dynein


Ari J. Firestone, Joshua S. Weinger, Maria Maldonado, Kari Barlan, Lance. D. Langston, Michael D. O’Donnell, Vladimir I. Gelfand, Tarun M. Kapoor, and James K. Chen


The AAA+ ATPase motor cytoplasmic dynein regulates a diverse range of cellular functions, including mitotic spindle assembly, organelle trafficking, and ciliary and axonal transport. Since the dynamics of these processes are much faster than the action of reverse-genetic technologies, small-molecule modulators are essential tools for studying dynein-dependent biology. In the Apr. 5 issue of Nature, Firestone et al. reports the first chemical inhibitors of this minus-end-directed microtubule motor, which emerged from a high-throughput screen for Hedgehog pathway inhibitors. The benzoyl dihydroquinazolinone derivatives, collectively named “ciliobrevins” for their effects on primary cilia length, selectively inhibit cytoplasmic dynein 1 and 2, as demonstrated by their cellular phenotypes and actions on dynein function in vitro.