Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold

Jin, Xin; Merrett, James E.; Tong, Sheng; Flower, Bartholomew; Xie, Jianling; Yu, Rilei; Tian, Shuye; Gao, Ling; Zhao, Jiajun; Wang, Xuemin; Jiang, Tao; Proud, Christopher G.

doi:10.1016/j.ejmech.2018.10.070

Cited by 31 publications

(20 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitogen-Activated Protein Kinase-Interacting Kinase Inhibitors in the Clinic. A broad array of smallmolecule MNK1/2 inhibitors have been identified to date that encompass diverse chemotypes as represented by Dreas et al (2017), Matsui et al (2018), Jin et al (2019), andMishra et al (2019). Well studied MNK inhibitors include staurosporine, CGP57380, and the natural product, cercosporamide (Fig.…”

Section: Mitogen-activated Protein Kinase-interacting Kinase Inhibitorsmentioning

confidence: 99%

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

et al. 2020

View full text Add to dashboard Cite

show abstract

Section: Mitogen-activated Protein Kinase-interacting Kinase Inhibitorsmentioning

confidence: 99%

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

et al. 2020

View full text Add to dashboard Cite

show abstract

“…VNLG-152, a retinamide derivative, and its racemic form VNLG-152R degraded MNK1 and blocked eIF4E phosphorylation producing a decrease in colony formation, migration and invasion, inducing cell death by apoptosis and affecting the cell cycle in MDA-MB-231 and MDA-MB-468, and suppressed the growth of MDA-MB-231 tumor xenografts and in TNBC patient-derived xenograft (PDX) model [84][85][86]. Compound MNK-7g is able to inhibit eIF4E phosphorylation and to block the migration of MDA-MB-231 without affecting proliferation [99]. However, eIF4E involvement does not always occur after MNK inhibition, so the effect of the different inhibitors on the kinase could affect or not affect eIF4E.…”

Section: Mnk In Breast Cancermentioning

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

View full text Add to dashboard Cite

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.

show abstract

“… 28 , 29 Effort has been therefore devoted to the identification of novel selective MNK inhibitors. In recent years, compounds like eFT508 ( 3 ), 30 BAY1143269, 31 SEL-201, 7 ETC-206, 32 MNK-I1, 9 and the MNK-I1-derived MNK2 selective inhibitor MNK-7g 33 have been developed and tested in preclinical settings. Among those, currently, eFT508, BAY1143269, and ETC-206 are tested in clinical trials in oncology.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

et al. 2022

View full text Add to dashboard Cite

Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4- b ]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.

show abstract

Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold

Cited by 31 publications

References 37 publications

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

Pharmacological Manipulation of Translation as a Therapeutic Target for Chronic Pain

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

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Contact Info

Product

Resources

About