Nobiletin is an inhibitor of ERK with in a concentration-dependent manner [1].
Nobiletin, a citrus polymethoxy flavonoid isolated from citrus fruits, is shown to play an important role in the process of anti-inflammatory, anti-tumor invasion, proliferation, and metastasis in vitro and in animal studies.
Nobiletin is shown to have the ability to suppress tumor growth and metastasis. In human nasopharyngeal carcinoma cell lines (HONE-1 and NPC-BM), nobiletin treatment significantly inhibited cells invasion via inhibiting the phosphorylation of ERK1/2 [2]. When tested with rat C6 glioma cell, nobiletin was shown to inhibit cell proliferation via suppress ERK activity [1].
In mouse model with 5-min BCCAO-induced brain ischemia, treatment nobiletin (50 mg/kg) intraperitoneally for the consecutive 7 days significantly inhibited delayed neuronal death in the hippocampal CA1 neurons and improved contextual memory [3]. In MPTP-induced Parkinson mouse model, administration of Nobiletin (50mg/kg i.p.) intraperitoneally for 2 consecutive weeks improved motor and cognitive deficits [4].
When tested with human monocytic THP-1 cells, nobietin treatment blocked the TPA-enhanced activation of ERK1/2 with the concentration of 100 μM [5].
References:
[1].    Aoki, K., et al., Nobiletin induces inhibitions of Ras activity and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling to suppress cell proliferation in C6 rat glioma cells. Biol Pharm Bull, 2013. 36(4): p. 540-7.
[2].    Chien, S.Y., et al., Nobiletin inhibits invasion and migration of human nasopharyngeal carcinoma cell lines by involving ERK1/2 and transcriptional inhibition of MMP-2. Expert Opin Ther Targets, 2015: p. 1-14.
[3].    Yamamoto, Y., et al., Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation. Brain Res, 2009. 1295: p. 218-29.
[4].    Yabuki, Y., et al., Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience, 2014. 259: p. 126-41.
[5].    Eguchi, A., A. Murakami, and H. Ohigashi, Nobiletin, a citrus flavonoid, suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. FEBS Lett, 2006. 580(13): p. 3321-8.