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.

Table 2 Casein kinase 1-specific small molecule inhibitors tested for treatment effects on pancreatic carcinoma cells in vitro and in vivo

Inhibitor	IC50 CK1 (µmol/L)	Observed effects in cell culture and in vivo data	Ref.
IC261	1.000 ± 0.30 (CK1δ)	Reduced growth of ASPC-1, BxPC3, Capan-1, Colo357, MiaPaCa-2, Panc-1, Panc89, and PancTu-1 at 1.25 µmol/L concentration of IC261; Subcutaneous xenograft model using PancTu-2: reduced tumor size with IC261 or gemcitabine (no synergism with gemcitabine), downregulation of anti-apoptotic genes/upregulation of cell cycle- and cell death-associated regulators; Notable off target effects (affecting the cytoskeleton and ion channels)	[155,168,182-184,202]
compound 11b	0.004 ± 0.001 (CK1δ); 0.025 ± 0.004 (CK1ε); 0.010 (p38α)	Cytotoxic effects observed on Colo357 (EC50 = 3.5 ± 0.3 µmol/L) and Panc89 (1.5 ± 0.4 µmol/L)	[174]
compound 3c	1.600 (CK1δ/ε)	In a panel of cell lines only effective against Panc-1 (EC50 = 9.3 ± 0.0 µmol/L); Cytotoxic effects observed on A549 (lung carcinoma) and Hek293 (normal cells) significantly higher EC50 values	[175]
compound 2	0.070 ± 0.01 (CK1δkd); 0.520 ± 0.05 (CK1ε)	Cytotoxic effects observed on BxPC3 (EC50 = 0.11 ± 0.01 µmol/L), Colo357 (0.13 ± 0.02 µmol/L), MiaPaCa (0.26 ± 0.02 µmol/L), PancTu-1 (0.70 ± 0.02 µmol/L), and Panc-1 (0.35 ± 0.08 µmol/L); Cell line-specific effects observed in screening against a panel of 82 tumor cell lines	[178]
IWP-4	1.020 ± 0.13 (CK1δ); 7.070 ± 2.01 (CK1ε)	Cytotoxic effects observed on A818-6 (EC50 = 0.93 ± 0.07 µmol/L), MiaPaCa-2 (0.23 ± 0.01 µmol/L), Panc-1 (0.23 ± 0.02 µmol/L), Panc89 (0.58 ± 0.12 µmol/L), and Capan (0.23 ± 0.01 µmol/L); Inhibition of Wnt signaling (Wnt3A overexpression, autocrine/paracrine) with IC50 = 0.71 ± 0.38 µmol/L; Inhibition of Wnt signaling (Wnt3A-conditioned medium, autocrine/paracrine) with EC50 = 1.47 ± 0.55 µmol/L
SR-3029	0.044 (CK1δ); 0.260 (CK1ε)	Cytotoxic effects observed on Panc-1 (EC50 = 0.023 µmol/L), MiaPaCa2 (0.370 µmol/L), and BxPC3 (0.131 µmol/L); Mouse pharmacokinetic studies with promising results for animal model use of SR-3029; Orthotopic xenograft model using Panc-1, reduced tumor size using SR-3029 and/or gemcitabine (synergism with gemcitabine due to upregulation of dCK)	[152,180]

CK1: Casein kinase 1; EC₅₀: Half maximal effective concentration; IC₅₀: Half maximal inhibitory concentration.