Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

Cherian, Joseph; Nacro, Kassoum; Poh, Zhi Ying; Guo, Samantha; Jeyaraj, Duraiswamy A.; Wong, Yun Xuan; Ho, Melvyn; Yang, Huihui; Joy, Joma; Kwek, Zekui Perlyn; Liu, Boping; Wee, John Liang Kuan; Ong, Esther; Choong, Meng Ling; Poulsen, Anders; Lee, May Ann; Pendharkar, Vishal; Ding, Li; Manoharan, Vithya; Chew, Yun Shan; Sangthongpitag, Kanda; Lim, Siak Piang; Ong, S. Tiong; Hill, Jeffrey; Keller, Thomas H.

doi:10.1021/acs.jmedchem.5b01712

Cited by 16 publications

(31 citation statements)

References 34 publications

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“…There may be limitations with an MNK1 selective approach as MNK2 can function in a compensatory fashion. A dual MNK inhibitor has been reported to be in Phase 1 clinical trial in Singapore . A selective and potent dual MNK1/2 inhibitor represents a new therapeutic opportunity; yet, to date, compounds to definitively assess this potential have remained elusive.…”

Section: Discussion and Conclusionmentioning

confidence: 99%

Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Reich¹,

Sprengeler²,

Chiang³

et al. 2018

J. Med. Chem.

141

136

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Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

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Section: Discussion and Conclusionmentioning

confidence: 99%

Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Reich¹,

Sprengeler²,

Chiang³

et al. 2018

J. Med. Chem.

141

136

View full text Add to dashboard Cite

show abstract

“…Second, we showed that treating HFD-fed WT mice with a specific MNK inhibitor, ETC-206 [ 44 ], also prevented weight gain and liver fat accumulation, even after these mice commenced the HFD. These data demonstrate that the effect of disabling MNK function is due to the loss of its activity, not simply of the proteins performing another type of function (which has been observed for certain other MAP kinase-activated protein kinases, e.g., [ 45 ]), and importantly, that it does not reflect a change that occurs earlier during development.…”

Section: Discussionmentioning

confidence: 99%

Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity

Sandeman

Kang

Wang

et al. 2020

Molecular Metabolism

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Objectives Diet-driven obesity is increasingly widespread. Its consequences pose major challenges to human health and health care systems. There are MAP kinase-interacting kinases (MNKs) in mice, MNK1 and MNK2. Studies have demonstrated that mice lacking either MNK1 or MNK2 were partially protected against high-fat diet (HFD)-induced weight gain and insulin resistance. The aims of this study were to evaluate the phenotype of mice lacking both MNKs when given an HFD, to assess whether pharmacological inhibition of MNK function also protects against diet-induced obesity (DIO) and its consequences and to probe the mechanisms underlying such protection. Methods Male wild-type (WT) C57Bl6 mice or mice lacking both MNK1 and MNK2 (double knockout, DKO) were fed an HFD or control diet (CD) for up to 16 weeks. In a separate study, WT mice were also given an HFD for 6 weeks, after which half were treated with the recently-developed MNK inhibitor ETC-206 daily for 10 more weeks while continuing an HFD. Metabolites and other parameters were measured, and the expression of selected mRNAs and proteins was assessed. Results MNK-DKO mice were almost completely protected from HFD-induced obesity. Higher energy expenditure (EE) in MNK-DKO mice was observed, which probably reflects the changes in a number of genes or proteins linked to lipolysis, mitochondrial function/biogenesis, oxidative metabolism, and/or ATP consumption. The MNK inhibitor ETC-206 also prevented HFD-induced weight gain, confirming that the activity of the MNKs facilitates weight gain due to excessive caloric consumption. Conclusions Disabling MNKs in mice, either genetically or pharmacologically, strongly prevents weight gain on a calorie-rich diet. This finding likely results from increased energy utilisation, involving greater ATP consumption, mitochondrial oxidative metabolism, and other processes.

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“…The use of imatinib with MNK inhibitors prevents eIF4E phosphorylation in vivo with an antiproliferative effect that could help to combat late-stage disease and to understand other pathways and cellular processes that are dysregulated by Bcr-Abl [119]. In addition, pharmacologic targeting of MNK and mTORC1 kinases, employing rapamycin together with novel MNK inhibitors (MNK1/2 53-54 or MNKI-4 and MNKI- 57) or niclosamide (an anthelminthic drug), abolished cell growth by triggering cell apoptotic death and abrogated eIF4E phosphorylation, which may offer a new therapeutic opportunity [76,96,110,121].…”

Section: Mnk In Hematological Cancersmentioning

confidence: 99%

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

Pinto-Díez

Ferreras-Martín

Carrión-Marchante

et al. 2020

IJMS

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The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

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Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

Cited by 16 publications

References 34 publications

Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

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