Recent developments of protein kinase inhibitors as potential AD therapeutics

Abstract

Present Alzheimer’s disease (AD) therapies suffer from inefficient effects on AD symptoms like memory or cognition, especially in later states of the disease. Used acteylcholine esterase inhibitors or the NMDA receptor antagonist memantine address one target structure which is involved in a complex, multifactorial disease progression. So the benefit for patients is presently poor. A more close insight in the AD progression identified more suggested target structures for drug development. Strategies of AD drug development concentrate on novel target structures combined with the established ones dedicated for combined therapy regimes, preferably by the use of one drug which may address two target structures. Protein kinases have been identified as promising target structures because they are involved in AD progression pathways like pathophysiological tau protein phosphorylations and amyloid β toxicity. The review article will shortly view early inhibitors of single protein kinases like glycogen synthase kinase (gsk3) β and cyclin dependent kinase 5. Novel inhibitors will be discussed which address novel AD relevant protein kinases like dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Moreover, multitargeting inhibitors will be presented which target several protein kinases and those which are suspected in influencing other AD relevant processes. Such a multitargeting is the most promising strategy to effectively hamper the multifactorial disease progression and thus gives perspective hopes for a future better patient benefit.

Tau physiology and pathomechanisms in frontotemporal lobar degeneration

“…It is thought that one reason for the abnormal increase in tau phosphorylation might be an imbalance in the activity or regulation of kinases and phosphatases. Among the kinases, glycogen synthase-3 (GSK3), cyclin-dependent kinase 5, the MAPK family composed of p38, extracellular-regulated kinase and c-Jun N-terminal kinase, and microtubule-affinity regulating kinase (MARK) have been shown to have a role and are considered as candidates for therapy (reviewed in Lee et al 2011;Tell and Hilgeroth 2013;Medina and Avila 2015). Interestingly, tau phosphorylation pathways seem to be evolutionarily conserved, as revealed by a study of 2N4R human tau overexpression in Drosophila, that described tau hyperphosphorylation via the involvement of the GSK3 homologue shaggy or Sgg (Jackson et al 2002).…”

Therapeutic strategies for the treatment of tauopathies: Hopes and challenges

“…Among these, the most well-studied and arguably most validated are GSK-3β and CDK5. It is beyond the scope of this brief review to summarize all of the data supporting the involvement of these kinases in tauopathies, and the reader is referred to recent reviews focused on tau phosphorylation and inhibitors of putative tau kinases [50, 51]. However, it can be briefly noted that both GSK-3β and CDK5 co-localize with tau tangles in AD brain [52–55], and there are convincing data showing that altered expression of GSK-3β [56–58] or p25 [59, 60], an activator of CDK5, affect tau pathology in transgenic (tg) mouse models.…”

Tau-Based Therapeutic Approaches for Alzheimer's Disease - A Mini-Review

“…Kinases involved in tau phosphorylation include glycogen synthase kinase 3 (GSK-3β), cdk5, p38, JNK, CK and DYRK1A [11]. Lithium and valproate have been shown to inhibit GSK and when given to Tg models reduce tau related pathology [13]; however, this effect was not corroborated in small clinical trials for both compounds [14;15].…”