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

Abstract

More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old painkiller (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC 50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC 50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers.

PAK1-blockers: Potential Therapeutics against COVID-19

“…Thus, via Click Chemistry (CC), 292 we have boosted its cell-permeability over 500 times (with IC 50 around 293 5-24 nM against B15F10 melanoma and A549 lung cancer cells, respec-294 tively) [29]. The resultant potent PAK1-blocker, called 1,2,3-triazolyl 295 ester of Ketorolac (15 K), suppresses both growth and metastasis of 296 chemo-resistant human pancreatic cancer xenogrfats in mice with IC 50 297 below 0.1 mg/kg/day, and causes no side effect even at 5 mg/kg/day 298 [30]. Thus, 15 K could be used not only for pancreatic cancer therapy, 299 but also for therapy of infectious diseases caused by coronavirus (COVID-300 19) and many other deadly viruses in the future.…”

Chemical evolution for taming the ‘pathogenic kinase’ PAK1

“…Notably, 90% of human pancreatic cancers are resistant to chemotherapies such as gemcitabine (GEM), and their chemoresistance is mainly the result of chemo-induced abnormal activation of PAK1 [18]. Remarkably, 15 K suppresses growth and metastasis of GEM-resistant human pancreatic cancer xenografts in mice with an IC 50 below 0.1 mg/kg/day, causing no side effect in mice even with doses of 5 mg/kg/day [19].…”

Therapies Against COVID-19: a Running to a Treatment

“…Thus, "Toradol" could be applied for the treatment of PAK1-dependent coronaviral infection. The resultant potent PAK1-blocker, called 1,2,3-triazolyl 295 ester of Ketorolac (15 K), suppresses both increase and metastasis of chemo-resistant human pancreatic cancer xenografts in mice with IC50 < 0.1 mg/kg/day, and causes no side effect even at 5 mg/kg/day Therapies against COVID- 19 298 [280]. Thus, 15 K could be applied not only for pancreatic cancer therapy but also for therapy of infectious diseases caused by a coronavirus (COVID300 19) and many other dangerous viruses in the future.…”