C-Jun N-terminal Kinase (JNK) Inhibitor Development for Stroke

C-Jun N-terminal kinase (JNK) is a key mitogen-activated protein kinase (MAPK) associated with inflammatory processes in many diseases. JNK is considered a major stress-responsive kinase that can be activated by various brain injuries and is involved in neuronal damage triggered by reperfusion-induced oxidative stress. Studies on new therapeutic targets for neuroinflammation and neuropathic pain have identified JNK as a promising target for stroke, as it reduces neuroinflammation in vivo and in vitro. Experimental studies have shown that JNK-IN-8, a highly specific JNK inhibitor, is a promising agent for the prevention of ischemic brain injury as it suppresses neuroinflammation and improves neurological function by inhibiting JNK/NF-κB.

Fig.1. JNK-IN-8 improves functional recovery after stroke. (Zheng, et al., 2020)

Our JNK Inhibitor Development Services

With a comprehensive understanding of the mechanisms that regulate the inflammatory process following brain injury, our scientists are committed to developing effective stroke therapeutics. Ace Therapeutics provides reliable JNK inhibitor development services to help clients develop stroke drugs that reduce neuroinflammation.

Our services cover the entire JNK inhibitor discovery and development process, from target identification to preclinical studies. By providing end-to-end services, we ensure the seamless progression of JNK inhibitors from early discovery through preclinical development.

Design and Optimization of JNK Inhibitors

We use X-ray crystallography or nuclear magnetic resonance (NMR) to obtain high-resolution structures of active and inactive forms of JNKs. These structures provide templates for rational drug design. In addition, we use computational docking methods to screen a large library of small molecules that bind to the JNK binding site. We provide reliable pharmacophore models that capture the essential features of known JNK inhibitors for more efficient screening of compound libraries.

We can help clients design more potent and selective JNK inhibitors. Lead compounds are iteratively modified to improve binding affinity, specificity, and drug-like properties. We use computational tools such as molecular dynamics simulations to predict the stability and interaction of compounds binding to JNKs.

Evaluation of JNK Inhibitors in Experimental Stroke Models

We have established transient middle cerebral artery occlusion (tMCAO) models to evaluate the efficacy and safety of JNK inhibitors.

• Neurological deficit scores: the modified neurological severity score (mNSS) score.
• Behavioral tests: including the baton twirling test for motor coordination, the open field test for general activity and anxiety, and the Morris water maze test for spatial learning and memory.
• TTC staining to measure infarct volume.
• Assess apoptosis and necrotic cell death using the TUNEL assay, cystatinase activity assay, and propidium iodide staining.
• Assess the expression levels of JNK pathway components and downstream targets using specific antibodies.
• Measure levels of total and phosphorylated JNK, c-Jun, and other related proteins to confirm pathway inhibition.
• Evaluate the absorption, distribution, metabolism, and excretion (ADME) of JNK inhibitors to optimize dosing regimens.

Using a comprehensive, iterative approach that integrates in vitro and in vivo, our drug development team helps clients design and optimize JNK inhibitors as promising stroke therapeutics. If you are interested in our services, please do not hesitate to contact us!

1. Zheng, J., et al. (2020). JNK-IN-8, ac-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke. Journal of cellular physiology, 235(3), 2792-2799.