Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Kościuczuk, Ewa M.; Saleiro, Diana; Kroczyńska, Barbara; Beauchamp, Elspeth M.; Eckerdt, Frank; Blyth, Gavin T.; Abedin, Sameem; Giles, Francis J.; Altman, Jessica K.; Platanias, Leonidas C.

doi:10.1182/blood-2016-02-698704

Cited by 42 publications

(42 citation statements)

References 32 publications

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“…Our study, and the work of others (38,39,48,49), strongly support the preclinical development of MNK1/2 inhibitors for the treatment of patients with melanoma, and potentially other malignancies harboring KIT aberrations.…”

Section: Discussionsupporting

confidence: 74%

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Yao

Guo

Yang

et al. 2017

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 74%

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Yao

Guo

Yang

et al. 2017

Journal of Clinical Investigation

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“…Recent findings in a mouse lymphoma model demonstrate that the phosphorylated form of eIF4E is required for the translation of a subset of mRNAs that oppose apoptosis and favor tumorigenesis [13,21,30,[40][41][42]. The role of the MNKs has been linked to the pathogenesis of many cancers [43,44]. PAK2 can interfere with the MNK1/2-eIF4G interaction by phosphorylating the MNKs on specific threonine and serine residues resulting in decreased affinity for eIF4G [21].…”

Section: Mapk-interacting Kinasesmentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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“…Assays were performed as previously described (Beauchamp et al., , ; Colamonici et al., ; Kosciuczuk et al., ). Briefly, 300‐500 U937 or MV4‐11 cells were plated in methylcellulose (MethoCult™ H4434 Classic w/o EPO, Stem Cell Technologies) and grown for 7 days to assess the effects of drugs on leukemic progenitor (CFU‐L) colony formation.…”

Section: Methodsmentioning

confidence: 99%

Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening

et al. 2019

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Mnk kinases (Mnk1 and 2) are downstream effectors of Map kinase pathways and regulate phosphorylation of eukaryotic initiation factor 4E. Engagement of the Mnk pathway is critical in acute myeloid leukemia (AML) leukemogenesis and Mnk inhibitors have potent antileukemic properties in vitro and in vivo, suggesting that targeting Mnk kinases may provide a novel approach for treating AML. Here, we report the development and application of a mutation‐based induced‐fit in silico screen to identify novel Mnk inhibitors. The Mnk1 structure was modeled by temporarily mutating an amino acid that obstructs the ATP‐binding site in the Mnk1 crystal structure while carrying out docking simulations of known inhibitors. The hit compounds display activity in Mnk biochemical and cellular assays, including acute myeloid leukemia progenitors. This approach will enable further rational structure‐based drug design of new Mnk inhibitors and potentially novel ways of therapeutically targeting this kinase.

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Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

Cited by 42 publications

References 32 publications

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Discovery of novel Mnk inhibitors using mutation‐based induced‐fit virtual high‐throughput screening

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