The development of an isoform-specific JNK3 inhibitor

Abstract

Mitogen-activated protein kinases (MAPK) are involved in a variety of signal transduction mechanisms as a response to a wide range of cellular stress stimuli. The ASK/MKK/JNK protein kinase cascade is involved in such signal transduction. The dysfunction of these cascades has been identified to impact downstream signaling effectors linked with the onset of neurodegeneration and cancer. c-Jun N-terminal kinases (JNK) are attractive therapeutic targets due to the rising interest in developing treatment for these diseases. Among the ten JNK isoforms (JNK1a/ß-1/2; JNK2a/ß-1,2; JNK3a-1/2), the two JNK3 isoforms' tissue distribution are near exclusive to the Central Nervous System (CNS). The objective of this work is to develop an isoform specific JNK3 inhibitor based on the structural protein interactions of JNK3 with its upstream kinases. Based on preliminary kinase assays comparing JNK3a2 and JNK2a2, it was supported that the novel Maltose Binding Protein (MBP)-fusion peptide inhibitor MBP-NJ40 was successful in isoform specificity in favor of JNK3a2. Another novel MBP-fusion peptide inhibitor, MBP-NJ20, was also investigated in its efficacy to inhibit JNK3a2. The half-maximal inhibitory concentration (IC50) of both MBP-NJ40 and MBP-NJ20 when analyzed were comparable to each other. This suggests that these inhibitors are successful novel candidates for controlled inhibition of JNK3a2.