JNK-IN-8

JNK-IN-8 is a covalent and highly selective JNK1/2/3 inhibitor with well validated activity in cells. The JNK family of kinases (also known as the stress-activated protein kinases, SAPK) play a significant role in the cellular response to cytokines and environmental stress. The literature surrounding these targets is vast, with JNK inhibition possibly being of utility in cancer, diabetes, Alzheimer’s disease and endometriosis. Unfortunately, the literature is also sometimes confusing and contradictory. Good small molecule tools like JNK-IN-8 are essential to the study of these important targets. JNK-IN-8 should prove a useful tool when used alongside other validated JNK inhibitors including bentamapimod, XG-102 and tanzisertib.     

This is a potent JNK1/2/3 inhibitor with some off target activity (MNK2, FMS at 200-500 nM).

JNK-IN-8 is an imatinib-derived pan-JNK inhibitor (biochemical IC50 values: 4.7 nM (JNK1), 18.7 nM (JNK2), 1 nM (JNK3)). Its covalent-irreversible binding mode is reasonable validated by X-ray structures and protein mass spectroscopy of close analogues. While showing high potency in biochemical assays on the isolated JNKs, the compound suffers from a surprisingly low inhibitory activity in a cellular environment (IC₅₀ 300-500 nM). Kinome-wide screening revealed several highly potent off target hits, but most of them could not be validated in subsequent IC₅₀ or Kd determinations (e.g., FMS and MNK2, ~200-300 nM). JNK-IN-8 may serve as a chemical probe in cells to investigate unselective JNK inhibition. It should be used with caution along with another positive control compound.