Evaluation of ciliobrevins paper

I have evaluated the following paper for Faculty of 1000:

Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein.
AJ Firestone, JS Weinger,…, TM Kapoor, JK Chen Nature 2012 Mar 18
PMID 22425997 DOI 10.1038/nature10936

The F1000 evaluation can be found here (£/€/$): http://f1000.com/14237961

This paper identifies and characterizes a series of small molecule inhibitors of the dynein motor. This work is significant as this represents only the second example of selective targeting of a member of the AAA+ ATPase family by a selective small molecule inhibitor, the first being inhibition of p97 by DBeQ {1}. These ‘ciliobrevins’ are benzoyl dihydroquinazolinone derivatives and are identified as inhibitors of dynein in an assay of Hedgehog (Hh) signalling, which occurs through primary cilia. The small molecules effectively block Hh signalling and localization of Arl13b to primary cilia (an assay for primary cilia formation). When cilia are formed, these ciliobrevins cause an accumulation of cargo (such as IFT88) at the distal tip, consistent with a defect in retrograde transport within the cilia. Dynein-2 is known to be the motor for retrograde transport along the ciliary axoneme. Together, these data indicate effective inhibition of dynein-2 function. These reagents have the potential to elucidate the role of dynein-2 in the very early stages of cilia formation. The authors also demonstrate that the ciliobrevins inhibit the more widely used motor dynein-1, effectively validating this in assays of mitotic spindle function, organelle motility, and in vitro assays. Further data are entirely consistent with the ciliobrevins competing for ATP binding and thereby inhibiting the ATPase activity of the motor. Specificity, it is shown by comparative analysis with a number of other AAA+ ATPases. Given that crystallography has achieved high resolution structures of p97 and the dynein motor, one might also expect some key atomic structures that could define why these compounds are selective in each case.

Please note that this is a distinct nomenclature to that of ‘ciliabrevin’, used previously for another inhibitor of cilia function {2}.

{1} Chou et al. Proc Natl Acad Sci U S A 2011, 108:4834-9 [PMID:21383145].
{2} Engel et al. Cytoskeleton 2011, 68:188-203 [PMID:21360831].