PAK Research Center, Australia
Ph.D. from University of Tokyo (in Pharmaceutical Sciences) in 1972. Research Associate at NIH (1973-80), Group leader at Max-Planck-Institute for Biochemie (1980-1984). Senior Scientist at Yale University and UCSD (1985-88). Laboratory Head at Ludwig Institute for Cancer Research (Melbourne Branch) (1988-2006). Visiting Professor at Hamburg University Hospital (2006-2007). Manager at PAK Research Center in Melbourne (2007-present).
PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase that is responsible for a wide variety of diseases/disorders such as cancers, neurofibromatosis (NF), Alzheimer’s disease (AD), diabetes (type 2), hypertension, a variety of infectious and inflammatory diseases, epilepsy, schizophrenia, depression, autism, and obesity. In addition, PAK1 shortens the healthy lifespan (1), and is essential for PDGF-dependent melanogenesis as well (2), suggesting that PAK1-blockers could be elixirs and skin-whitening cosmetics. It should be worth noting that all herbal AMPK activators are PAK1-blockers as well as HSP (heat shock protein)-inducers, as the anti-oncogenic kinase LKB1 activates AMPK as well as inactivates PAK1, and activates HSP genes through the transcription factor FOXO that is activated by AMPK and inactivated by PAK1 (1). Thus, the potential market value of natural or synthetic PAK1-blockers/AMPK activators/ HSP-inducers would be huge, and pharmaceutical giants such as Pfizer, Roche, Novartis and Astrazeneca recently started developing potent PAK1-blockers. However, major problem of these synthetic PAK1-blockers for clinical application is their poor water-solubility and cell-permeability. Here we present a new trick for robustly boosting the anti-cancer activity and cell-permeability of several COOH-bearing PAK1-blockers without any loss of their water-solubility. According to Barry Sharpless (2001 Nobel-laureate), any COOH-bearing compounds could be esterized with water-soluble 1,2,3-Triazolyl alcohol through copper-catalyzed “Click Chemistry” (CC) in a high yield. Thus, in 2015, we have successfully synthesized 1,2,3-Triazolyl esters of two herbal PAK1-blcokers (artepillin C, ARC, and caffeic acid, CA) from propolis, and an old pain-killing PAK1-blocker (ketorolac) sold by Roche. The resultant esters (15A, 15C and 15K) are highly cell-permeable and their anti-cancer activity is 100 times of ARC, over 400 times of CA, and over 500 times of Ketorolac, respectively (3). Among these esters, 15K is the most potent anti-cancer/PAK1-blocker with IC50 =24 nM (against A549 lung cancer) and IC50=6 nM (against B16F10 melanoma) cells (3). Furthermore, 15K inhibits angiogenesis in ovo (fertilized eggs) with IC50 = 1 n mole/egg (Ahn, MK et al, unpublished observation). Currently we are testing if 15K extends the healthy lifespan of C. elegans, as does Okinawa propolis (OP) (4). Regarding OP and edible sea cucumber (SC), the major anti-cancer ingredients of OP and SC are geranylated flavonoids (Nymphaeols A-C), and a sulfated saponin called Frondoside A (FRA), respectively. We recently found that both Nymphaeols and FRA directly inhibit PAK1 in vitro with IC50 10 mM and 1 mM, respectively, in a selective manner (Nguyen, BC et al, unpublished observation).