Abstract 948: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Although targeting the BCR-ABL kinase with tyrosine kinase inhibitors (TKI) is effective in chronic phase (CP) CML, targeting BCR-ABL alone is not sufficient to treat late-stage or blast crisis (BC) CML. In BC CML, granulocyte macrophage progenitors (GMPs) acquire the ability to function as leukemic stem cells (LSCs), and are thought to act as a reservoir for TKI resistance. While long-term remission in BC CML is possible with allogeneic stem cell transplantation, only a minority of patients are eligible for transplantation, and may experience high morbidity and mortality. Safe and effective BC CML therapy will likely have to target the BC LSC population to ensure long-term disease control. Recent studies have shown the importance of the MAP kinase interacting serine/threonine kinase (MNK1/2)-eukaryotic translation initiation factor 4E (eIF4E) axis in sustaining BC LSC self renewal. Thus, a single agent which inhibits both BCR-ABL and MNK1/2 kinase simultaneously represents a rational approach to target BC LSCs. Such an agent should be able to distinguish between normal hematopoietic stem cells (HSC) and LSCs. Here, we report the discovery, structure activity relationships, pharmacokinetic properties, and biochemical characteristics of dual MNK1/2 and BCR-ABL inhibitors, ETC-027 and ETC-219. These compounds are able to prevent eIF4E phosphorylation, BCR-ABL-driven growth and proliferation of BC CML cells, as well as inhibit the MNK-eIF4E-dependent self-renewal function of BC LSCs, while leaving normal HSCs untouched. Citation Format: Joseph Cherian, Kassoum Nacro, Zhi Ying Poh, Samantha Guo, Melvyn Ho, Haiyan Yang, Sharon Lim, Meng Ling Choong, Jun Li Ding, Joma Kanikadu Joy, Zekui Perlyn Kwek, Boping Liu, Hongqian Esther Ong, Vishal Pendharkar, Anders Poulsen, May Ann Lee, Kanda Sangthongpitag, Charles Chuah, Tiong S. Ong, Jeffrey Hill, Thomas H. Keller, Alex Matter. Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2014-948