Evaluated: UA62784 Is a cytotoxic inhibitor of microtubules, not CENP-E.

This paper recently caught my eye. I evaluated it for Faculty of 1000.

S Tcherniuk,S Deshayes,V Sarli,G Divita,A Abrieu (2011)
UA62784 Is a cytotoxic inhibitor of microtubules, not CENP-E.
Chem Biol 18, 5.
PMID: 21609844 DOI: 10.1016/j.chembiol.2011.03.006

F1000 evaluation at: http://f1000.com/14267299

This paper caught my eye as it alters our perception of the target of the small molecule inhibitor UA62784. Previously characterised as a CENP-E inhibitor, the authors here show that it is in fact a potent inhibitor of microtubule dynamics and has no inhibitory effect on CENP-E in vitro.

While clearly of interest to those in the mitosis field, this work also has great importance for those (including us) who have used such compounds for other reasons. It also provides a nice chemical biology story relating to the importance of target validation. Indeed, there are two companion pieces relating to this issue that I would also recommend reading {1,2}.

References:

{1} Chemical inhibitors: the challenge of finding the right target.
Calligaris D, Lafitte D
Chemistry & Biology 2011 May 27; 18(5): 555-7

{2} Motor-dependent and -independent roles of CENP-E at kinetochores: the cautionary tale of UA62784.
Maiato H, Logarinho E
Chemistry & Biology 2011 Jun 24; 18(6): 679-80

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
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10936.html

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}.

References:
{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].