Beta-Elemene : a herbal PAK1-blocker that up-regulates PAK1-interacting protein 1

  According to a recent paper by a Chinese group, beta-elemene from Curcuma increases the radio-sensitivity of cancer cells by blocking the oncogenic/ageing kinase PAK1 (1).  Both radiation and UV irradiation are known to activate PAK1, making cancer cells more resistant to any anti-cancer drugs. 

How does beta-elemene block PAK1?  They found that it up-regulates a PAK1-inhibitor called "PAK1-interacting protein 1" which binds the N-terminal 70 amino acid motif of PAK1 (2).  

Unfortunately, however, the IC50 of beta-elemene against cancer cells in cell culture is rather high, around 300 micro M. Thus, it is unlikely that be-elemene is clinically useful for cancer therapy.  Thus, another Chinese group developed a far more potent "dimethylpiperazine"  derivative beta-elemenecalled IIi whose IC50 against cancer cells in cell culture is around 3 micro M (3).

  
References:

1。Liu JS¹, Che XM¹, Chang S¹, Qiu GL¹, He SC¹, Fan L¹, Zhao W¹, Zhang ZL¹, Wang SF¹ β-elemene enhances the radiosensitivity of gastric cancer cells by inhibiting Pak1 activation. World J Gastroenterol. 2015 Sep 14; 21(34): 9945-56.

2. Xia C¹, Ma W, Stafford LJ, Marcus S, Xiong WC, Liu M. Regulation of the p21-activated kinase (PAK) by a human Gbeta -like WD-repeat protein, hPIP1. Proc Natl Acad Sci U S A. 2001;  98(11): 6174-9.

3.  Ding XF¹, Shen M, Xu LY, Dong JH, Chen G.

13,14-bis(cis-3,5-dimethyl-1-piperazinyl)-β-elemene, a novel β-elemene derivative, shows potent antitumor activities via inhibition of mTOR in human breast cancer cells. Oncol Lett. 2013; 5(5): 1554-1558.

Another "Holy Grail": A geo-specific esterase that cleaves the Arg-ester of ST2002 at position 3 or 9

Staurosporine (ST) is a highly cell permeable but non-specific kinase inhibitor. To make this compound highly specific for the oncogenic/ageing kinase PAK1, ST should bear a bulky side chain at position 3 or 9 to exclude all kinases except for PAK1. Furthermore, it has been known for more than a decade, OH at position 3 (or 9)=ST2001, but not both (ST2002), boosts the anti-PAK1 activity by 50 times (reaching IC50=1 nM). ST is not water-soluble, but if you attach the basic amino acids such as Arg and Lys, to position 3 or 9 (or both), it becomes water-soluble and more cell-permeable.  Considering these factors, we are currently designing a potent, water-soluble, highly cell-permeable PAK1-specific ST derivatives called "ST3009".

ST2001 was found in a marine organism more than a decade ago, but this organism has vanished from the ocean sadly.  Chemical synthesis of ST2001 is possible, but its yield is so low, and economically unfeasable. The major product of ST (chemical) hydroxylation is ST2002 in which both 3 and 9 is hydroxylated.  Unfortunately, ST2002 has no anti-PAK1 activity.

Thus, to make the ST3009 (golden egg) efficiently, we have to esterize ST2002 at both positions 3 and 9 chemically, making ST3003 first, and then cleave only one of these ester bonds geo-selectively by a specific esterase, eventually yielding the ST3009.  This sort of "geo-specific" esterase is our "Holy Grail" in the forthcoming ST3009 project.