Nguyen Binh Cao Quan, Taira Nozomi, Tawata Shinkichi
Department of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Kagoshima University.
Drug Discov Ther. 2014 Dec;8(6):238-44. doi: 10.5582/ddt.2014.01045.
The p21-activated kinase 1 (PAK1) is emerging as a promising therapeutic target, and the search for blockers of this oncogenic/aging kinase would be potentially useful for the treatment of various diseases/disorders in the future. Here, we report for the first time the anti-PAK1 activity of compounds derived from three distinct Okinawa plants. 5,6-Dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) from alpinia inhibited directly PAK1 more strongly than mimosine and mimosinol from leucaena. Cucurbitacin I isolated from bitter gourd/melon also exhibited a moderate anti-PAK1 activity. Hispidin, a metabolite of DK, strongly inhibited PAK1 with the IC50 = 5.7 μM. The IC50 of three hispidin derivatives (H1-3) for PAK1 inhibition ranges from 1.2 to 2.0 μM, while mimosine tetrapeptides [mimosine-Phe-Phe-Tyr (MFFY) and mimosine-Phe-Trp-Tyr (MFWY)] inhibit PAK1 at nanomolar level (IC50 of 0.13 and 0.60 μM, respectively). Thus, we hope these derivatives of hispidin and mimosine could be used as potential leading compounds for developing far more potent anti-PAK1 drugs which would be useful for clinical application in the future.
p21激活激酶1（PAK1）正逐渐成为一个有前景的治疗靶点，寻找这种致癌/衰老激酶的阻滞剂可能对未来治疗各种疾病/病症有用。在此，我们首次报道了源自三种不同冲绳植物的化合物的抗PAK1活性。来自山姜属植物的5,6-脱氢卡瓦因（DK）和二氢-5,6-脱氢卡瓦因（DDK）比来自银合欢属植物的含羞草碱和含羞草醇更强烈地直接抑制PAK1。从苦瓜/甜瓜中分离出的葫芦素I也表现出适度的抗PAK1活性。DK的一种代谢产物漆黄素强烈抑制PAK1，IC50 = 5.7 μM。三种漆黄素衍生物（H1-3）对PAK1抑制的IC50范围为1.2至2.0 μM，而含羞草碱四肽[含羞草碱-苯丙氨酸-苯丙氨酸-酪氨酸（MFFY）和含羞草碱-苯丙氨酸-色氨酸-酪氨酸（MFWY）]在纳摩尔水平抑制PAK1（IC50分别为0.13和0.60 μM）。因此，我们希望这些漆黄素和含羞草碱的衍生物可作为潜在的先导化合物，用于开发更有效的抗PAK1药物，这将对未来的临床应用有用。
