Recent developments are explored by us in the discovery of JNK inhibitors and their potential in treating human disease. We first focus on GW0742 small molecule, ATP aggressive JNK inhibitors as summarised in. Our preliminary discussion centers on SP600125 manufactured by Signal Pharmaceuticals/Celgene. Furthermore, currently a short breakdown of an increasing quantity of other small particle ATP aggressive JNK inhibitors now defined in the published literature. We then examine the recent developments in the use of ATP low competitive JNK inhibitory peptides. These inhibitors are also featured in. Finally, we consider questions that arise with the growth of JNK inhibitors and their possible therapeutic application. These concerns centre on the controls had a need to establish nature of activities of JNK inhibitors, whether JNK isoformselective inhibitors are feasible or desirable, Eumycetoma whether other materials have off target effects to inhibit JNK, and what problems accompany the use of JNK specific inhibitors. Further work will be had a need to address these problems, though the demonstrated effectiveness of the existing era of JNK inhibitors in improving outcomes in disease models shows that this further attempt will be worthwhile. In late 2001, the small molecule JNK inhibitor, SP600125 one, was noted following the testing of a proprietary library for inhibitors of JNK2 activity towards the d Jun transactivation domain. The chemical composition of SP600125 is shown in, along side the houses of other small molecule inhibitors of JNK discussed in subsequent parts of this review. The extremely planar character of SP600125 and poor solubility in aqueous solution, both consequences of its anthrapyrazolone core structure, were noted in its original description. JNK inhibition by SP600125 was more Dinaciclib SCH727965 observed to be reversible and ATP competitive, displaying IC50 values for JNK inhibition in the product range of 40?90 nM with N300 fold selectivity over the relevant mitogen activated protein kinases, ERK1 and p38 2 and between 10 fold and 100 fold selectivity over another 14 protein kinases tested. These results suggested high affinity and specific interactions of SP600125 with deposits in the JNK ATP binding site. These relationships of SP600125 with JNK have already been further explored following the co crystallisation of SP600125 with JNK3. The resulting structure : 1PMV is found in, where the JNK3 residues not preserved in the associated MAPK, p38 2, have been highlighted. These remains make a narrow ATP binding pocket in JNK that covered the planar SP600125 molecule and were believed to contribute to the uniqueness of SP600125 towards JNK over the p38 MAPKs.