R-9630 Rottlerin, >98%
Related Terms : [Mallotoxin]
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- M.W. 516.54
- M.I. 12: 8429
- M.I. 14: 8272
- An excellent and very thorough review of the numerous and confounding biological activities of rottlerin is now available: Soltoff, Stephen P. "Rottlerin: an inappropriate and ineffective inhibitor of PKCδ." Trends Pharm. Sci. 28: 453-458 (2007). This review makes it clear that, unfortunately, there may now be hundreds of published articles that contain erroneous, rottlerin-based conclusions about PKCδ functions.
- Initially, rottlerin was reported to inhibit PKCδ (IC50 = 3-6 µM) 5- to 10-fold more potently than PKCα or PKCβ and 13- to 33-fold more potently than PKCε, ζ, or η. It also inhibited CAM kinase III at 3-6 µM, was inactive against SRC kinase, and was a weak inhibitor of PKA and casein kinase II. Biochem. Biophys. Res. Comm. 199: 93-98 (1994).
- At best, these potency differences of 5- to 13- fold are quite modest, pharmacologically speaking, and in practice would require careful manipulation of concentrations to produce meaningful differentiation of PKC isotype effects.
- Much more serious problems with rottlerin have come to light. In an extensive study of protein kinases and inhibitors, rotterlin failed to show any PKC inhibitory activity at all against the α and δ PKC isotypes, even at 20 µM and very low ATP concentrations and under a variety of conditions. It was, however, a potent inhibitor of MAPK-activated protein kinase 2, p38-regulated/activated kinase, protein kinase A, and glycogen synthase kinase 3-beta. Biochem. J. 351: 95-105 (2000). Thus, rottlerin does not appear to have any utility as a PKCδ-selective tool.
- Furthermore, rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation. J. Biol. Chem. 276: 37986-37992 (2001) and Endrocrinology 143: 3884-3896 (2002). This effect results in additional non-specific, confounding activities for rottlerin: Cancer Res. 63: 5118-5125 (2003).
- LC Labs has tested the purity of rottlerin obtained from the same source used in the BBRC article cited above, and many substantial impurities were found. Our highly purified product was free of these impurities, and we believe the rottlerin used in the Biochem. J. study is traceable to LC Labs. Thus, the original inhibitory activity of rottlerin for PKCδ may have been due to an impurity not present in the later study.
- There are now many published studies that cite the effects of rottlerin as a basis for conclusions about the cellular roles of PKCδ. These conclusions now appear to be incorrect. We would appreciate receiving from our readers any information that might shed more light on this topic, so that we can inform other researchers of the latest findings regarding rottlerin's actual biological properties.
- In the past, we produced rottlerin by purifying it from raw material from a source in Europe, but that source no longer sells crude rottlerin. Given the highly questionable utility of rottlerin as a kinase inhibitor, we decided not to pursue alternative sources of raw materials. Therefore, we have now discontinued all sales of rottlerin.