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An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis
Journal article   Peer reviewed

An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis

Theodosia Teo, Yuchao Yang, Mingfeng Yu, Sunita K C Basnet, Todd Gillam, Jinqiang Hou, Raffaella M Schmid, Malika Kumarasiri, Sarah Diab, Hugo Albrecht, …
European journal of medicinal chemistry, Vol.103, pp.539-550
2015
DOI: https://doi.org/10.1016/j.ejmech.2015.09.008
PMID: 26408454

Abstract

Dose-Response Relationship, Drug Drug Discovery Drug Evaluation, Preclinical Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Models, Molecular Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Structure-Activity Relationship
Deregulation of protein synthesis is a common event in cancer. As MAPK-interacting kinases (Mnks) play critical roles in regulation of protein synthesis, they have emerged as novel anti-cancer targets. Mnks phosphorylate eukaryotic initiation factor 4E (eIF4E) and promote eIF4E-mediated oncogenic activity. Given that the kinase activity of Mnks is essential for oncogenesis but is dispensable for normal development, the discovery of potent and selective pharmacological Mnk inhibitors provides pharmacological target validation and offers a new strategy for cancer treatment. Herein, comprehensive in silico screening approaches were deployed, and three thieno[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine derivatives were identified as hit compounds. Further chemical modification of thieno[2,3-d]pyrimidine derivative 3 has given rise to a series of highly potent Mnk2 inhibitors that could be potential leads for the treatment of acute myeloid leukemia.

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Source: InCites

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Collaboration types
Domestic collaboration
Citation topics
1 Clinical & Life Sciences
1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis
1.25.803 PI3K/AKT/mTOR Pathway
Web Of Science research areas
Chemistry, Medicinal
ESI research areas
Chemistry
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