Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease

Abstract

Pharmaceutical approaches to slow the progression of Alzheimer's disease (AD) have focused primarily on reducing production or increasing clearance of amyloid b peptide (Ab Key words: Alzheimer; tau; cyclin-dependent kinase 5; CDK5; glycogen synthase kinase 3; GSK3; c-Jun N-terminal kinase; JNK; p38 kinase; Casein kinase 1; CK1; Rho kinase; Rock; p21-activating kinase; Pak AMYLOID AND TAU BRAIN PATHOLOGIES HAVE DIRECTED KINASE TARGET EFFORTSAlzheimer's disease (AD) is characterized by the accumulation in hippocampal and cortical brain regions of two insoluble, proteinaceous aggregates. The amyloid plaque is composed primarily of extraneuronal deposits of amyloid b (Ab), which is cleaved from the amyloid precursor protein (APP) by two intracellular proteases, b-and g-secretase [Selkoe, 1991;Sisodia and St George-Hyslop, 2002;Vetrivel and Thinakaran, 2006] (Fig. 1). a-Secretase cuts approximately in the middle of Ab after lysine-16, precluding its formation. The neurofibrillary tangle (NFT) is composed primarily of intraneuronal deposits of hyperphosphorylated tau protein (ptau) (Fig. 2) Iqbal and Grundke-Iqbal, 2006;Hyman et al., 2005], thought to result from an imbalance of kinase and phosphatase activity. Together, amyloid deposits and neurofibrillary tangles define the AD brain, yet, are not unique to AD [Askanas and Engel, 2007;Hutton, 2001]. How these insoluble proteins contribute to the inflammation, neuronal and synaptic loss and behavioral decline that is also characteristic of AD is unknown. These pathologies have directed drug discovery efforts to slow the progression of AD, with the goal of reducing levels of Ab and ptau. Animal model systems have been developed incorporating increased expression of APP and tau, and with these systems, upstream targets such as secretases and kinases have been studied. This review will focus on a number of protein kinase targets implicated in AD pathology and the DDR Published online in Wiley InterScience (www.interscience.wiley. com).

DISC1 as a therapeutic target for mental illnesses

“…For example, the S713 residue of DISC1 can be phosphorylated by both protein kinase A (PKA) and cycline-dependent kinase 5 (cdk5) [42]. Cdk5 inhibitors CP-681301 and CP-668863 have been considered as potential therapeutics for Alzheimer’s disease [81], and may also target other neural and cognitive dysfunctions [82]. The role of phosphorylation and other post-translational modifications of DISC1 at the synapse remain elusive, but will likely play key roles in synaptic transmission.…”

Targets and Small Molecules Against Tauopathies. Part 1: From Genes to Soluble, Aggregation-Prone Tau Proteins

“…It is assumed that in pathological conditions some of them may increase their activity on tau, and/or that the activity of their phosphatase counterparts is reduced. Kinases are heavily popular as CNS targets [143], and several tau kinase inhibitors have entered clinical trials [144]. Kinases are heavily popular as CNS targets [143], and several tau kinase inhibitors have entered clinical trials [144].…”

“…A provocative chemotype-based analysis, focused on 17 heterocyclic cores and on their recurrence in potent GSK-3 inhibitors, can be accessed [296]. More details could also be found in four recent reviews [101,144,297,298]. More details could also be found in four recent reviews [101,144,297,298].…”

Dragon exploration system on marine sponge compounds interactions

“…CDKs (CDK1, CDK2, and CDK5) have been associated with tau hyperphosphorylation, amyloid precursor protein processing, and apoptosis due to the cell cycle deregulation in AD [31]. Therefore, the agents that block cyclins or CDKs may further block neurodegeneration in AD patients [32]. Thus, we can propose a hypothesis that variolins, being inhibitors of CDKs, could block neurodegeneration in AD.…”