1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of <i>C. elegans</i> by down-regulating PAK1 at nM levels

PAK Family Kinases Come of Age: Celebrating 40 Years of Discovery

“…Thus, we have managed to boost its cellpermeability 500 times by coupling the water-soluble 1,2,3-triazolyl alcohol through CC [15], producing a very potent PAK1-blocking ester called 15K with IC50 ranging 5-25 nM depending on cancer cell lines (Figure 3). We recently confirmed that 15K extends the healthy lifespan of C. elegans at 50 nM, and boosts the heat-endurance (survival after prolonged heat-shock) of this worm several times even at 10 nM (Figure 4), strongly suggesting that 15K could be a potent elixir (longevity-promoter) as well as cancer therapeutic [12,16].…”

“…Several compounds that directly inhibit PAK1 have been developed. Among them is IPA-3 that allosterically binds PAK1, instead of binding its ATP-binding pocket [16]. A series of FRAXs developed by Afraxis are potent ATP-antagonists relatively specific for the group 1 of PAK1 family [12].…”

Chemical evolution for taming the ‘pathogenic kinase’ PAK1

“…This esterization led to a great leap (>500 times) in the anti-PAK1 and anticancer properties of ketorolac [15]. The IC 50 of 15 K is in the range 5-24 nM against different cancer cell lines, and it increases the heat resistance of C. elegans by nine times even at 10 nM 35 C (nonpermissive temperature), inducing a heat shock gene called HSP16.2 via the longevity transcription factor FOXO, and concomitantly extends the healthy lifespan of this worm by 15-30% 20 C (permissive temperature) [17]. Facing the current climate crisis namely 'global warming or extreme heat' (e.g., frequent summer bushfires in California and the southern half of Australia), 15 K and other PAK1 blockers could provide us with a practical alternative (chemical evolution) of the genetic evolution (knockout of PAK1 gene) for our survival of the extreme heat, which might eventually lead to extinction of the whole animal kingdom from the surface of this planet (none of the plant kingdom carries the pathogenic PAK1 gene).…”

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice

“…Thus, via Click Chemistry, we have esterized ketorolac with the water-soluble 1,2,3-triazolyl alcohol, making 15K which is over 500 times more cell-permeable than ketorolac, and inhibits the growth of RAS-transformed lung cancer cell line (A549) with IC 50 around 24 nM. Furthermore, 15K was found to extend the healthy lifespan of C. elegans 15-30% at 50 nM (depending on the temperature) and boost its heat-resistance over 9 times (7). Thus, it is strongly suggested that 15K, a potent anti-cancer (anti-PAK1/anti-COX-2) and antiaging drug, could overcome the GEM-resistance of human pancreatic cancers without any serious sideeffects.…”