Abstract
Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.
Highlights
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blood–brain barrier (BBB) reflects the properties of two components: one forms a structural/physical barrier composed of endothelial cells and extremely tight intercellular junctions that regulate diffusion of solutes between blood and brain; the other is a biochemical/selective barrier due to the presence of specific transport proteins expressed on the luminal and abluminal plasma membranes of the endothelial cells able to act as important central nervous system (CNS) gatekeepers, selectively increasing brain permeability to essential nutrients or effectively preventing foreign compounds’ permeation [5]
There is an ever-growing need to find drugs able to reach the brain in an adequate concentration for engaging CNS targets and modulating complex and interconnected signaling pathways linked to different neurological disorders
Summary
The human kinome plays a crucial role in many physiological events, and its dysregulation is associated with a large portion of multifactorial disorders, including cancer and neurodegenerative diseases. The rediscovery of “old molecules” fits with the need for poorly addressed therapeutic areas in which the CNS-related pathologies represent a leading field [11,12] Great examples in this scenario are saracatinib (1) and masitinib (2), which are two well-known inhibitors of FYN kinase firstly developed as anti-cancer agents. Abnormal phosphorylation of microtubule-associated protein τ at different sites, inclu3d.iτngHySpeerr/pThhorsprehsoirdyulaetsioinn Ser/Thr-Pro sequences, is one of the major pathological events in AD and other related neurodegenerative diseases, such as FTLD and additional dtaeugoepiennvaecetrlhnuatiAtdseiiobsinnnn[g5oAi8rSnDm,e5Ara9a/lD]nT.dph.ThIrohnotrehsevpeasirihbtdrornuoeroleyakrsltmiaenitndiaeotlnSnipeecurohs/rfotoTusmdhdperiihcg-eProesornrotoyeufrlsbaaetuthtqiilveuoee-enbandisoncissfeodesτcia,inisaisesgtseto,bhdnseeueptkwcroheofeytaeetshdnineFrhiTmτvyLepaaDrjteooardrpfnipfdnhfaeeoatruhsdeprodnolhtiotfoiigsobriitnycreaailslalll,aterdy and ntaourompaatlhτiessu[g58g,e59st].edThSeearb2n0o2r/m39a6l pahnodspThhorr2y0la5tiaomn oofnτgitshtheeckrietyicdarlivpehroosfpnheourryofilabtriiollnarsyites, whicdhegleeanderatotiotnhiensAeDqu. Ienstvriatrtoiokninoeftichsytpuderiepshoofstphhe obrinydlaintegdbeτtwineteon hmyipcerropthuobsuplheo-arysslaotceidated proteainnds naonrdmaitlsτ sseulgf-gaegstgerdegSeart2io0n2/i3n9t6oanNdFTThsr2[6050]a.mTohnegsethaegcgrirteicgaaltpehsotsrpighogreyrlaatiocnassciatedse, of biolowgihciachl pleraodcetosstehse, sτeqcuaescstardatei,onamofohnygpeortphheorssp, huoltriymlaatetedlyτ icnutolmminicartoitnugbuinle-nasesuorcoiantaeld cell deathp,robtreaiinns aatnrdopithsys,ealfn-adggcoreggnaittiiovneidnetoclNinFeT[s6[16]0.]. Τ overexpression has been reported to promote GSK-3β activation and mediate GSK-3β toxicity whereas, in τ absence, the neurodegenerative and cognitive phenotype observed in GSK-3β overexpressing mice proved to be ameliorated [65]
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