Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases, Ras or Raf proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit Raf kinases (e.g. Sorafenib) are successful antineoplastic agents against various types of cancer. MEK inhibitor cobimetinib has been investigated in pre-clinical lung cancer models in combination with inhibition of the PI3K pathway, where the two drugs lead to a synergistic response.
JNK kinases are implicated in the development of insulin resistance in obese individuals as well as neurotransmitter excitotoxicity after ischaemic conditions. Inhibition of JNK1 ameliorates insulin resistance in certain animal models. Mice that were genetically engineered to lack a functional JNK3 gene - the major isoform in brain – display enhanced ischemic tolerance and stroke recovery. Although small-molecule JNK inhibitors are under development, none of them proved to be effective in human tests yet. A peptide-based JNK inhibitor (AM-111, a retro-inverse D-motif peptide from JIP1, formerly known as XG-102) is also under clinical development for sensorineural hearing loss.
p38 was once believed to be a perfect target for anti-inflammatory drugs. Yet the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 kinases might be poor therapeutic targets in autoimmune diseases. Many of these compounds were found to be hepatotoxic to various degree and tolerance to the anti-inflammatory effect developed within weeks. An alternative approach is to evaluate the potential for targeting upstream MAPKs, such as ASK1. Studies in animal models of inflammatory arthritis have yielded promising results, and ASK1 has recently been found to be unique amongst the MAPKs in that it is inducible by inflammatory cytokines such as TNF-α.