Selective inhibitors for JNK signalling: a potential targeted therapy in cancer

Figures & data

Figure 1. JNK promotes cancer cell survival by modulating cancer cell initiation, invasion, proliferation, and migration.

Figure 2. The “break the brake” hypothesis of JNK during regulation of cancer cell survival.

Figure 3. Chemical structures of selective JNK inhibitors.

Table 1. Anticancer and other potential clinical applications of JNK inhibitors.

Inhibitor	Target	IC50	Clinical potentials	References
SP600125	JNKs	JNK1/2 = 40 nM; JNK3 = 90 nM	Anticancer potential for stomach cancer, oral squamous carcinoma, lung adenocarcinoma, cholangiocarcinoma, and colon carcinoma.	^65
AS601245	JNKs	JNK1 = 150 nM; JNK2 = 220 nM; JNK3 = 70 nM	Anticancer potential for colon cancer and T cell acute lymphoblastic leukaemia.	^71^,^72
AS602801	JNKs	JNK1 = 80 nM; JNK2 = 90 nM; JNK3 = 230 nM	Induces apoptosis of cancer stem cells.	^76
JNK-IN-1	JNKs	JNKs = 2.31 nM	Anticancer potential for skin cancer and attenuation of chronic colitis.	^93^,^96
BI-78D3	JNKs	JNKs = 280 nM	Anticancer potential for osteosarcoma.	^97
JNK-IN-8	JNKs		Sensitizes triple-negative breast cancer cells to lapatinib.	^73
Bi-78D3	JNKs		Blocks JNK-dependent Con A-induced liver damage; restores insulin sensitivity in mouse models of type 2 diabetes.	^84
Ginsenoside Rg1	JNKs		Protects against ischemia/reperfusion-induced liver damage.	^98
4-fluorophenyl isoxazoles	JNKs	JNK1 = 13 nM; JNK3 = 16 nM	A structure-activity relationship study was performed; however, the cellular potency and in vivo properties need to be improved.	^17
XG-102 (D-JNKI-1)	JNKs		31-D-amino-acid peptide; it is safe for the treatment of patients with post-surgery or post-trauma intraocular inflammation; protects against TNBS-induced colitis.	^99^,^100
4-quinolone analogues	JNKs	JNK1 = 62 nM; JNK2 = 170 nM	This compound shows excellent kinase selectivity and impressive efficacy in a rodent asthma model.	^101
CC-930	JNKs	JNK1 = 61 nM; JNK2 = 7 nM; JNK3 = 6 nM	Does not inhibit CYP450 enzymes significantly; it shows low toxicity, is well tolerated, and exposure is dose-proportional.	^94
Quinazoline	JNK3	JNK3 = 40 nM	Shows good brain penetration and pharmacokinetic (PK) properties and is a candidate for in vivo evaluation in the central nervous system (CNS)efficacy models.	^102
Triazolothione 1	JNK3	JNK3 = 1.07 nM	It has CNS properties.	^88
Pyridopyrimidinone Derivatives	JNK3	JNK3 = 15 nM	Clean CYP-450 inhibition profile; good microsomal stability; and good oral bioavailability.	^92
AV7	JNK1		It has the potential to treat of diabetes.	^86
D-PYC98	JNK1		A novel retro-inverso peptide; inhibits p38, and c-Jun Ser63 phosphorylation during hyperosmotic stress.	^41
Isoquinolone derivatives	JNK1	JNK1 = 86 nM	They can be novel therapeutic agents for heart failure without affecting blood pressure.	^85
JNK inhibitor IX (JNKi)	JNK2/3		Induce DNA fragmentation and apoptotic cell death in human Jurkat T cells.	^81

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