Microtubule affinity-regulating kinases are potential druggable targets for Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD.

Strategy for Lead Identification for Understudied Kinases

“…These kinases include some of the original targets for which pyrimidine-based inhibitors were prepared (JAK2, IKKε, TBK1, and ULK1), a more well-studied kinase that is potently inhibited by many analogs within this structural class (AURKB), and several understudied kinases, many of which are both on the IDG list (AAK1, BMP2K, DRAK1−2, MARK1−4, MLK1, MLK3, and NUAK1) and of interest in the neuroscience space. 14,15,17,[26][27][28][29] We profiled our pyrimidine series and the parent pyrimidines that influenced our design against this kinase panel at a single concentration (1 μM) in radiometric enzymatic assays at Eurofins at the Km = ATP for each kinase. Table 1 shows the results of this study, where % control is reported for each compound for each kinase and lower values indicate greater inhibition.…”

“…Highly selective compounds have the potential to be chemical probe candidates, and, as such, we chose to execute thorough enzyme profiling to validate or invalidate potential off-targets. Thus, for the 5 compounds in our library with an S10(1 μM) <0.002 (15,8,12,16, and 21) we followed-up on all kinases inhibited >65% at 1 μM in the scanMAX platform and/or inhibited >50% in our initial custom enzymatic profiling panel at Eurofins (Table 1). One exception to this was exclusion of AURKA follow-up for 21.…”

“…Results from these studies combined with the single-concentration enzymatic results from Table 1 are displayed in Table 3. Compounds in Table 3 are listed in order of their kinome-wide selectivity scores from most (15) to least (6) selective.…”

“…Observations of AD brains show a strong correlation between cognitive dysfunction and cortical neurofibrillary tangle density. [14][15][16] Mutations in tau have also been shown to cause a form of FTD. 16 Furthermore, with a characterized role in dendrite branching and spine development, understudied kinase AAK1 plays a role in several neurodegenerative disorders, including AD and Figure 1.…”

Structure Based Design and Molecular Docking Studies for Phosphorylated Tau Inhibitors in Alzheimer’s Disease

“…Several studies revealed that the involvement of tau in synaptic starvation and neurodegeneration is associated with the imbalanced states of phosphatases and kinases in a neuronal cell [10]. The tau is a harbor of kinase dependent residues, nearly 80 serine/threonine/tyrosine, and relays with malfunctions of microtubules in AD state [10,11,12]. The regulation of tau phosphorylation and kinase sites dependent studies were largely inspected in the past in order to understand the significance of p-tau sites and kinase-based expression in AD.…”