Abstract 2137: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia

Abstract

Abstract Chronic Phase Chronic Myelogenous Leukemia (CP-CML) is well treated with tyrosine kinase inhibitors (TKI) through BCR-ABL kinase modulation. However, TKI are ineffective for late-stage or blast crisis (BC) CML in which phase, granulocyte macrophage progenitors (GMPs) have acquired the ability to function as leukemic stem cells (LSCs), and are thought to act as a reservoir for TKI resistance with poor prognosis. An 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 of a potential BC-CML therapy that relies on the inhibition of MNK1/2 and BCR-ABL kinases using a dual specific MNK/ABL inhibitor. We will also report the in vitro and in vivo biological data, pharmacokinetic properties, and biochemical characteristics of such compounds. These compounds are able to prevent eIF4E phosphorylation, thus selectively inhibiting the MNK-eIF4E-dependent self-renewal function of BC-LSCs as a single agent while leaving normal HSCs unscathed. Citation Format: Joseph Cherian, Kassoum Nacro, Zhi Ying Poh, Samantha Guo, Melvyn Wai Tuck Ho, Haiyan Yang, Sharon Lim, Meng Ling Choong, Joma Kanikadu Joy, Perlyn Z. Zekui, Boping Liu, Esther Hongqian Ong, Vishal Pendharkar, Lijun Ding, 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 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2137.