Science: Current research status on RAC-PAK1 blockers, from propolis (CAPE) to 15K or DBQ-202

Back in late 1980s, a team at Columbia University in NY found that “propolis” (alcohol extract of bee-hives) suppresses the growth of cancer cells, and its major anti-cancer ingredient is CAPE (caffeic acid phenethyl ester). However, it remained unknown how CAPE inhibits selectively the growth of cancer cells without any effect on normal cell growth. In 1994 the first mammalian PAK1 was cloned by a team led by Dr. Ed Manser in Singapore. This kinase is closely related to myosin I heavy chain kinase isolated from a soil amoeba by us at NIH in 1977, and both are activated by GTPases called RAC and CDC42.
Around the turn of this century, we and others found that RAC/CDC42-PAK1 signaling pathway is essential for cancer growth, but not normal cell growth. Then around 2004, we found that both caffeic acid (CA) and CAPE inhibit RAC with IC50=10-100 micro M, thereby blocking the oncogenic PAK1 signaling pathway. Almost same time, a team at Cincinnati Children Cancer Center led by Dr. Yi Zheng, found a synthetic chemical called NSC23766 also inhibits directly RAC with IC50 =25-50 micro M.
Since then, this RAC-PAK1 field has been vastly advanced, and towards the end of 2015 we developed a highly cell-permeable RAC inhibitor called 15K (1,2,3-triazolyl ester of ketorolac) from an old pain-killer (Ketorolac) via Click Chemistry (CC) , that inhibits the growth of cancer cells with IC50 ranging 5-24 nM (depending on cell lines), and suppresses both growth and metastasis of chemo-resistant pancreatic cancer xenografts in mice with IC50 far below 0.1 mg/kg daily, surely with no side effect even with 5 mg/kg daily. 15K is over 500 times more cell-permeable than Ketorolac without any loss of water-solubility!
Around 2017, a team at Puerto Rico University led by Dr. Cornelis Vlaar developed a new RAC inhibitor called MBQ-167, related to NSC23766, which suppresses the growth of cancer cells with IC50 around 100 nM, and supresses the cancer gowth in mice with IC50 around 1 mg/kg daily. Obviously 15K is at least 10 times more potent than MBQ-167 both in cell culture and in vivo.
Interestingly I recently noticed that 15K and MBQ-167 happen to share a very similar over-all chemical structure, but noticed a critical difference in side chain as well. Thus, we are planning to develop a hopefully far more potent RAC inhibitor called MBQ-202, ortho-methoxy derivative of MBQ-167, based on our valuable experience from 15K. MBQ-202 could be 100-500 times more cell-permeable than MBQ-167!?
In addition, I would like to remind readers that these RAC-PAK1 blockers would be useful for treating COVID-19 patients as well. For detail, see the following review of ours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166201/
Lastly, we found a decade ago that PAK1-deficient mutant of C. elegans (nematode) lives 60% longer (and 10 times more heat-resistant) than the wild-type, clearly indicating that these PAK1-blockers would help us (human beings and any other animals) to survive during the current “global-warming” era...