MAP kinase-interacting serine/threonine-protein kinases 1 and 2 (MNK1/2) as targets for the development of oncologic, metabolic and CNS therapies have recently gain a tremendous amount of interest. This, in conjunction with the increasing knowledge on the impact of mRNA translation reprogramming and control in tumorigenesis. MNK1/2 are serine and threonine kinases that phosphorylate eukaryotic translation initiation factor 4E (eIF4E) on Ser209. eIF4E and especially, phosphorylated eIF4E play an important role in oncogenic mRNA translation. Overexpression of phosphorylated eIF4E drive oncogenesis, tumor progression with often a poor prognosis as seen with patients in Blast crisis chronic myeloid leukemia (BC-CML). Imatinib (GleevecTM), a marketed BCR-ABL tyrosine kinase inhibitor (TKI), has not only galvanized targeted therapy but has specifically revolutionized the treatment of early stage or chronic phase (CP) chronic myeloid leukemia (CML). Unfortunately, a proportion of CP-CML patients do not respond to Imatinib treatment and will progress to BC-CML. A consistent feature in these patient samples is an elevated level of phosphorylated eIF4E. Consequently, our strategy to treat to BC-CML is to develop MNK inhibitors that will moderate the level of phosphorylated eIF4E. Here, we report our hits finding schemes, as well as our hit to lead optimization process. Structure activity relationships, pharmacokinetics properties, and efficacies studies will be presented. Our data demonstrate that drug-like molecules can be developed to potently and specifically inhibit the MNK kinases. We will also show that simultaneous inhibition of MNK and BCR-ABL is effective at preventing BCR-ABL-driven growth and proliferation, as well as inhibiting the MNK-eIF4E-dependent self-renewal function of BC leukemic stem cells. We have identified a selective Mnk1/2 inhibitor ETC-206 currently in clinical trial.

Mnk1/2 and Abl inhibitions for the treatment of blast crisis chronic myelogenous leukemia

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.