MAP Kinase Phosphatases in Cancer and Heart Regeneration

Mitogen-activated protein kinase phosphatases (MKP) play important roles in cancer, immune response, and myocardial infarction.  The MKP active sites are shallow and contain a catalytic cysteine that is susceptible to oxidation; thus MKPs are widely being regarded as undruggable.  With collaborators in the Departments of Developmental Biology, Computational and Systems Biology, and Pharmaceutical Sciences, we have identified an allosteric inhibitor of MKP1 and MKP3 that is devoid of developmental toxicity and enhances heart regeneration in zebrafish.   Most recent data document that the lead agent selectively kills cancer cells by apoptosis and sensitizes cells to immune cell kill.  (Molina et al. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages.

Nat Chem Biol. 2009;6:680-7;  Korotchenko et al. In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. Chembiochem. 2014;15:1436-45. Kaltenmeier et al., A Tumor Cell-Selective Inhibitor of Mitogen-Activated Protein Kinase Phosphatases Sensitizes Breast Cancer Cells to Lymphokine-Activated Killer Cell Activity. J Pharmacol Exp Ther. 2017;361(1):39-50. PubMed PMID: 28154014.  PMCID: PMC5363763)