The c-Jun N-terminal kinases (JNKs) signaling pathway is associated with the pathogenesis of several diseases including cancer. Most JNK inhibitors target the highly conserved ATP binding site. This conservation promotes cross-reactivity and toxicities that may limit their potential as drugs. These drawbacks motivate the search for protein-interaction inhibitors with acceptable specificity and potency.We applied a virtual screening (VS) workflow to discover novel scaffolds for JNK inhibitors targeting the JNK-JIP (JNK Interacting Protein) interaction. (-)-Zuonin A was identified as an inhibitor of JNK, exhibiting 100-fold selectivity for the JNKs over other MAP kinases. (-)-Zuonin A was characterized extensively as JNK pathway manipulator both in vitro and in cellular breast cancer models.The JNK2 isoform has been reported to regulate breast cancer cell migration. Accordingly, we engineered peptides derived from the JIP scaffolds connected through a flexible linker to either the N-terminus of an inverted TATsequence (JIP10-?-TATi), or to a poly-arginine sequence (JIP10-?-R9) enabled the potent inhibition of JNK2 (IC50~90 nM) with 10-fold selectivity over JNK1/3. Both peptides inhibited the migration of Polyoma Middle-T Antigen Mammary Tumor (PyVMT) cells through the selective inhibition of JNK2.References:(1) Kaoud, T. S.  ; Park, H.; Mitra, S.; Yan, C.; Tseng, C. C.; Shi, Y.; Jose, J.; Taliaferro, J. M.; Lee, K.; Ren, P.; Hong, J.; Dalby, K. N. ACS Chem Biol 2012 .(2) Kaoud, T. S.  ; Yan, C.; Mitra, S.; Tseng, C. C.; Jose, J.; Taliaferro, J. M.; Tuohetahuntila, M.; Devkota, A.; Sammons, R.; Park, J.; Park, H.; Shi, Y.; Hong, J.; Ren, P.; Dalby, K. N. ACS Med Chem Lett 2012  , 3, 721.(3) Kaoud, T. S.  ; Mitra, S.; Lee, S.; Taliaferro, J.; Cantrell, M.; Linse, K. D.; Van Den Berg, C. L.; Dalby, K. N. ACS Chem Biol 2011  , 6, 658.

Manipulating JNK signaling by protein interaction blockers that inhibit breast cancer cell migration

245th National Meeting (2013)

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