hydroxy-aryl-aldehyde based IRE1 RNase inhibitors (4µ8C and others)

A note on hydroxy-aryl-aldehyde based IRE1 RNase inhibitors (4µ8C and others):

4µ8C and other reactive hydroxy-aryl-aldehyde based IRE1 RNase inhibitors are powerful tools for inhibiting downstream signaling in the IRE1 branch of the UPR in cultured cells (for example, Cross et al. 2012). In their favour is a defined mechanism of action involving reactivity with a key lysine residue in IRE1a's active site (Tomasio et al, 2013; Sanches et al 2014). However this chemical reactivity, required for the inhibitory effect on the enzymatic activity of IRE1, also markedly limits their utility in animal experiments, where rapid clearance (likely due to first pass metabolism in liver and possibly other tissues), renders them essentially ineffective. 

In cell based experiments, these features seem less important as sustained inhibition of XBP1 splicing can be observed over long tracks of time. However here the pitfall are the off target effects, presumably arising from reactivity of lysines on one or other key proteins. A recent study on the effects of 4µ8C on insulin secretion (Sato et al. 2017) highlights the potential importance of such off-target, IRE1a-independent, effects of 4µ8c and STF-083010. Thus for black box physiology, where the goal is to discover new things to say about IRE1a – the compounds are useful, but only in relief: If used at high enough concentration (sufficient to block all XBP1 splicing) they can effectively exclude a role for IRE1a - RNase activity in this, that or the other but only weakly suggest such a role.

David Ron

Cambridge, 24 June 2014

REF:

Cross, B. C. S., Bond, P. J., Sadowski, P. G., Jha, B. K., Zak, J., Goodman, J. M., et al. (2012). The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proceedings of the National Academy of Sciences of the United States of America, 109(15), E869–78. http://doi.org/10.1073/pnas.1115623109

Tomasio, S. M., Harding, H. P., Ron, D., Cross, B. C. S., & Bond, P. J. (2013). Selective inhibition of the unfolded protein response: targeting catalytic sites for Schiff base modification. Molecular bioSystems, 9(10), 2408–2416. http://doi.org/10.1039/c3mb70234k

Sanches, M., Duffy, N. M., Talukdar, M., Thevakumaran, N., Chiovitti, D., Canny, M. D., et al. (2014). Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nature Communications, 5, 4202. http://doi.org/10.1038/ncomms5202

Sato, H., Shiba, Y., Tsuchiya, Y., Saito, M., & Kohno, K. (2017). 4μ8C Inhibits Insulin Secretion Independent of IRE1α RNase Activity. Cell Structure and Function, 42(1), 61–70. http://doi.org/10.1247/csf.17002