Abstract
Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer’s and Parkinson’s diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC50 = 4.8 μM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation. This analysis led us to confirm the hypothesised binding mode of VS6 and to identify a new derivative that is about 6-fold more active than VS6 (compound 3, IC50 = 0.76 μM).
Highlights
Fyn kinase is a member of the Src family kinases (SFKs), which is one of the largest and most studied families of non-receptor tyrosine kinases (TKs) due to the implications of its members in oncogenesis and cancer development
Fyn is involved in axon–glial signal transduction, oligodendrocyte maturation and myelination[2]; it stimulates the synthesis of abundant myelin associated oligodendrocytic basic protein, influencing oligodendroglial morphological differentiation[3], and it is implicated in synapse formation and post-synaptic excitatory transmission[4]
Fyn was found to be implied in T-cell development, homoeostasis, activation and to have a critical role in thymocyte development together with Lck kinase, which is another member of the SKFs5
Summary
Fyn kinase is a member of the Src family kinases (SFKs), which is one of the largest and most studied families of non-receptor tyrosine kinases (TKs) due to the implications of its members in oncogenesis and cancer development. Due to its several physiological roles, an aberrant expression of Fyn kinase or a dysregulation of its activity is involved in the development and progression of different pathological conditions. Due to its involvement in cancer and CNS pathologies, the identification of selective Fyn inhibitors is an expanding field of study. We recently developed a VS study mixing ligand-based and receptor-based approaches, which allowed the identification of a novel small-molecule inhibitor of Fyn kinase (compound VS6) with low micromolar potency[20]. We report the computational investigation of VS6 binding mode into Fyn catalytic site, carried out through consensus docking, MD simulations and binding free energy evaluations, followed by a preliminary structural optimisation aimed at the development of novel potent Fyn inhibitors
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