Inhibitory effects of SEL201 in acute myeloid leukemia

// Ewa M. Kosciuczuk 1 , 2 , 3 , * , Aroop K. Kar 1 , 4 , * , Gavin T. Blyth 1 , 2 , Mariafausta Fischietti 1 , 2 , Sameem Abedin 1 , 2 , 5 , Alain A. Mina 1 , 2 , Rebekah Siliezar 1 , Tomasz Rzymski 6 , Krzysztof Brzozka 6 , Elizabeth A. Eklund 1 , 2 , 3 , Elspeth M. Beauchamp 1 , 2 , 3 , Frank Eckerdt 1 , 7 , Diana Saleiro 1 , 2 and Leonidas C. Platanias 1 , 2 , 3 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA 2 Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 3 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA 4 Division of Hematology/Oncology/Stem Cell Transplantation, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA 5 Division of Hematology and Oncology Department of Medicine Medical College of Wisconsin, Milwaukee, Wisconsin, USA 6 Ryvu Therapeutics, Krakow, Poland 7 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA * These authors contributed equally to this work Correspondence to: Leonidas C. Platanias, email: l-platanias@northwestern.edu Keywords: acute myeloid leukemia; MNK; eIF4E; kinase inhibitor; SEL201 Received: October 17, 2019     Accepted: December 02, 2019     Published: December 24, 2019 ABSTRACT MAPK interacting kinase (MNK), a downstream effector of mitogen-activated protein kinase (MAPK) pathways, activates eukaryotic translation initiation factor 4E (eIF4E) and plays a key role in the mRNA translation of mitogenic and antiapoptotic genes in acute myeloid leukemia (AML) cells. We examined the antileukemic properties of a novel MNK inhibitor, SEL201. Our studies provide evidence that SEL201 suppresses eIF4E phosphorylation on Ser209 in AML cell lines and in primary patient-derived AML cells. Such effects lead to growth inhibitory effects and leukemic cell apoptosis, as well as suppression of leukemic progenitor colony formation. Combination of SEL201 with 5’-azacytidine or rapamycin results in synergistic inhibition of AML cell growth. Collectively, these results suggest that SEL201 has significant antileukemic activity and further underscore the relevance of the MNK pathway in leukemogenesis.