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Author
Fité i Martí, Lídia
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Abstract
Cancer is one of the leading causes of death worldwide. In particular, breast cancer is the most common among women, affecting 2.1 million women each year. The eukaryotic translation initiation factor 4E (eIF4E) plays an important role in mRNA translation. Through its role in stimulating protein synthesis, eIF4E has been implicated in tumorigenesis and phosphorylation at Ser209 has been shown to be necessary for the oncogenic potential of eIF4E. This phosphorylation is only catalyzed by the MNK1 / 2 protein kinases (MAP kinase interacting kinases 1 and 2).
High levels of phosphorylated eIF4E expression can alter cell growth control and are associated with human cancers. Phosphorylation of eIF4E is necessary for tumor transformation but dispensable for normal development and, therefore, pharmacological inhibition of MNKs can provide a way to act on tumor cells without affecting normal tissues.
Seeing the promising results of EB1 as an inhibitor of MNKs, in this project, the synthesis of new pyrazole [3,4-b] pyridinic systems derived from EB1 is proposed as possible candidates for MNK inhibitors with the aim of improving the activity.
The interaction between ligand and receptor has been studied and different ligands have been proposed. The different areas of the pocket have been considered to study positions where hydrogen bonds could form between the ligand and the receptor residues, taking into account the affinity values. From here, the candidates to be synthesized have been selected.
Necessary methodologies have been optimized for the synthetic routes explored and new functional groups have been introduced in this type of structure.
4 molecules have been synthesized, which have been sent to test against the MNK1 and MNK2 kinases.
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