Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

Chronic myeloid leukemia
(CML) is a myeloproliferative disease
caused by bcr-abl1, a constitutively active tyrosine
kinase fusion gene responsible for an abnormal proliferation of leukemic
stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term
relief to CML patients. However, for a proportion of them, BCR-ABL1
inhibition will become ineffective at treating the disease, and CML
will progress to blast crisis (BC) CML with poor prognosis. BC-CML
is often associated with excessive phosphorylated eukaryotic translation
initiation factor 4E (eIF4E), which renders LSCs capable of proliferating
via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently,
a selective inhibitor of MNK1/2 should reduce the level of phosphorylated
eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering
the proliferation of BC LSCs. We report herein the structure–activity
relationships and pharmacokinetic properties of a selective MNK1/2
inhibitor clinical candidate, ETC-206, which in combination with dasatinib
prevents BC-CML LSC self-renewal in vitro and enhances
dasatinib antitumor activity in vivo.