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.
Most recently a collaborative effort with City of Hope has shown that reactivation of Erk signaling by MKP inhibition in malignant B-cells subverts transformation https://www.nature.com/articles/s41586-020-2513-4
Molina G, Vogt A, Bakan A, Dai W, de Oliveira PQ, Znosko W, Smithgall TE, Bahar I, Lazo JS, Day BW, Tsang M. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat Chem Biol. 2009;6(8):680-7. PMCID: PMC2771339. (# equal contribution) PMID: 19578332 PMCID: PMC2771339 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771339/
Korotchenko, VN, Saydmohammed M, Vollmer LL, Bakan A, Sheetz K, Debiec KT, Greene KA, Agliori, CS, Bahar I, Day BW., Vogt A, Tsang M. In Vivo Structure-Activity Relationship Studies Support Allosteric Targeting of a Dual Specificity Phosphatase. Chembiochem 2014;15(10): 1436-1445. PMID: 24909879 PMCID: PMC4118675 https://pubmed.ncbi.nlm.nih.gov/24909879/
Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Polonen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinaniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, Muschen M. Signalling input from divergent pathways subverts B cell transformation. Nature. 2020;583(7818):845-51. PubMed PMID: 32699415; PMCID: PMC7394729. https://doi.org/10.1038/s41586-020-2513-4