Optimization of selective mitogen-activated protein kinase Interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia
Yang, H., Chennamaneni, L. R., Ho, M. W. T., Ang, S. H., Tan, E. S. W., Jeyaraj, D. A., Yeap, Y. S., Liu, B., Ong, E. H., Joy, J. K., Wee, J. L. K., Kwek, P., Retna, P., Dinie, N., Nguyen, T. T. H., Tai, S. J., Manoharan, V., Pendharkar, V., Low, C. B., ... Nacro, K. (2018). Optimization of selective mitogen-activated protein kinase Interacting kinases 1 and 2 inhibitors for the treatment of blast crisis leukemia. Journal of Medicinal Chemistry, 61(10), 4348-4369. Advance online publication. https://doi.org/10.1021/acs.jmedchem.7b01714
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abll, 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.