In search of novel tau kinase inhibitors and their role in alzheimer’s therapy

Ubiquitously expressed, kinases are key enzymes that regulate the cellular metabolism by catalyzing the phosphorylation of serine/threonine/tyrosine residues by transferring a γ-phosphate moiety from ATP. The dysregulation or an imbalance in kinase signaling pathways can produce pathological changes that result in disease. For example, Alzheimer’s (AD), the most common neurodegenerative disease, is usually caused by hyper-phosphorylation of Tau kinases. Tau is a microtubuleassociated protein that is significantly expressed in healthy neurons and plays a significant role in the neuronal cytoskeleton stabilization. Structurally, the Tau protein is divided into four domains: an acidic region in the N-terminal part, a proline-rich region, a microtubule-binding domain (MBD) containing four repeat units and a C-terminal region respectively. Interestingly, each repeat domain in the MBD contains a conserved consensus motif KXGS, which is readily phosphorylated, resulting in the destabilization of the neuronal cytoskeleton. Consequently, phosphorylation disrupts Tau-dependent cellular functions, thereby promoting Tau dissociation from microtubules, forming neurofibrillary tangles (NFT), a pathological hallmark of AD. Recent studies have shed light on the pathological phosphorylation sites responsible for Tau aggregation. This information has led to research involving the development of inhibitors targeting these kinases. In AD, Tau phosphorylation precedes Tau aggregation and the subsequent formation of NFT. Several families of kinases are known to be involved and are well documented and reviewed elsewhere. This chapter focuses on the key kinases, namely CLK1, DYRK1A, CDK5, GSK3β and CK1δ as data indicate that targeting these proteins may have therapeutic promise against AD. Moreover optimization techniques, including chemical modifications of small heterocyclic nucleus, that are currently being used for the development of highly potent, safe and selective inhibitors has been discussed here.