Lesson 3: Tackle Tyr-kinases (ETK, JAK2, FYN), only upstream of PAK1

I have pointed out that three Tyr-kinases (ETK, JAK2 and FYN) are essential for the full activation of PAK1 in cells. Interestingly, none of these Tyr-kinases is involved in the activation of other members of PAK family (PAK 2-6).  In other words, inhibiting ETK, JAK2 or FYN would block selectively the activation of PAK1 only, and would not affect the remaining five members of PAK family. Furthermore, an ETK inhibitor called AG879 or GL-2003, a JAK2 inhibitor called cucurbitacin I, and a FYN-inhibitor called PP1/PP2,  block the activation of PAK1 in cells, mostly with the IC50 ranging 5-10 nM, clearly indicating that these Tyr-kinase inhibitor are highly potent (cell-permeable), and therefore would be very useful for clinical purposes such as cancer therapy. 

Thus, instead of developing (poorly cell-permeable) "PAK1-specific" inhibitors, we shall encourage "bright" (open-minded) scientists to tackle "PAK1-specific" activators (ETK, JAK2 and FYN) by these (or new) "highly cell-permeable" compounds (synthetic or natural).  You should push the boundary (Grenzgebiet) further for a great leap.  Why not?

We have recently patented a series of water-soluble PP1/PP2 derivatives which are potentially useful for clinical application. One of them called PP12 inactivates PAK1 by inhibiting FYN directly, and inhibits the growth of human colon and lung cancer cells, which carry the oncogenic K-RAS mutant, with the IC50 around 50 nM.  We believe PP12 would be potentially useful for therapy of pancreatic, colon, and lung cancers as well as brain tumors such as glioma　and NF tumors.