Stress-activated kinases as therapeutic targets in pancreatic cancer

Table 1 Small molecule inhibitors of stress-activated protein kinases tested for treatment effects on pancreatic carcinoma cells in vitro and in vivo

Inhibitor	IC50 (µmol/L)	Observed effects in cell culture and in vivo data	Ref.
JNK inhibitor II(SP600125)	0.040 (JNK1); 0.040 (JNK2); 0.090 (JNK3)	Antitumor effects in cancer cell lines of thyroid, stomach, lung, colon, pancreas, and brain	[104,185-189]
JNK inhibitor XVI(JNK-IN-8)	0.005 (JNK1); 0.019 (JNK2); 0.980 (JNK3)	Covalent binding to JNK inactivates kinase function; Sensitizes pancreatic cancer cells and triple negative breast cancer cells to 5-FU/FOLFOX and triple negative breast cancer cells to lapatinib treatment	[190-192]
Bentamapimod(AS602801)	0.080 (JNK1); 0.090 (JNK2); 0.230 (JNK3)	Cytotoxic effects observed on cancer stem cells derived from pancreatic cancer, non-small cell lung cancer, ovarian cancer, and glioblastoma	[103,193]
SB203580	0.034 (p38)	Synergistic effects observed in combination with cisplatin in vitro and in vivo; Inhibition of gemcitabine-induced apoptosis in combination therapy (tested on PK-1 and PCI-43 PDAC cell lines); IC50(p38) = 0.08-0.20 µmol/L in vivo)	[194-198]
SB202190	0.050 (p38α); 0.100 (p38β2); 0.600 (CK1)	Inhibition of gemcitabine-induced apoptosis in combination therapy (tested on PK-1 and PCI-43 PDAC cell lines); Inhibits resistance of colon cancer cell lines towards irinotecan	[93,197,199,200]
SB239063	0.044 (p38α and β)	Dose-dependent growth inhibition observed in three pancreatic cancer cell lines	[68,201]

CK1: Casein kinase 1; EC₅₀: Half maximal effective concentration; 5-FU: 5-fluorouracil; IC₅₀: Half maximal inhibitory concentration; JNK1/2/3: c-Jun N-terminal kinases 1, 2, and 3.