Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases

Abstract

Kinases are highly tractable drug targets that have reached unparalleled success in fields such as cancer but whose potential has not yet been realized in neuroscience. There are currently 55 approved small molecule kinase-targeting drugs, 48 of which have an anticancer indication. The intrinsic complexity linked to central nervous system (CNS) drug development and a lack of validated targets has hindered progress in developing kinase inhibitors for CNS disorders when compared to other therapeutic areas such as oncology. Identification and/or characterization of new kinases as potential drug targets for neurodegenerative diseases will create opportunities for the development of CNS drugs in the future. The track record of kinase inhibitors in other disease indications supports the idea that with the best targets identified small molecule kinase modulators will become impactful therapeutics for neurodegenerative diseases. This Review highlights the imminent need for new therapeutics to treat the most prevalent neurodegenerative diseases as well as the promise of kinase inhibitors to address this need. With a focus on kinases that remain largely unexplored after decades of dedicated research in the kinase field, we offer specific examples of understudied kinases that are supported by patient-derived data as linked to Alzheimer’s disease, Parkinson’s disease, and/or amyotrophic lateral sclerosis. Finally, we show literature-reported high-quality inhibitors for several understudied kinases and suggest other kinases that merit additional medicinal chemistry efforts to elucidate their therapeutic potential.

Kinase Signaling in Dendritic Development and Disease

“…The human genome encodes a total of 518 kinases (Manning et al, 2002). While genetic models and GWAS analyses have identified several kinase-encoding genes implicated in neurological disease (Krahn et al, 2020), there remains much to discover about kinase function in dendrite development and how their dysregulation contributes to neuronal disease. Unbiased mapping of kinase signaling that instruct distinct stages of dendritic growth may reveal novel pathways that can be further genetically dissected.…”

“…In addition to its effect on microtubule stability and synaptic function, hyperphosphorylated tau promotes Aβ toxicity mediated neuropathology (Ittner et al, 2010;Mairet-Coello et al, 2013), hence targeting tau hyperphosphorylation might prove to be a viable therapeutic strategy for AD. Several small molecule inhibitors targeting kinases that phosphorylate tau are currently in clinical trial for AD (Table 2) (Tell and Hilgeroth, 2013;Krahn et al, 2020).…”

“…Several protein kinases are genetically linked to neurological disorders. These include neurodevelopmental disorders such as autism spectrum disorder as well as neurodegenerative diseases such as Parkinson's disease, yet little is known about how dysfunction in kinase signaling leads to pathological states (Baltussen et al, 2017;Krahn et al, 2020). Phosphorylation mediated by kinases is countered by phosphatases, a large family of enzymes that catalytically remove phosphate groups from their substrates (Barford et al, 1998;Peng and Maller, 2010).…”

Strategy for Lead Identification for Understudied Kinases

“…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.…”

“…ALS. 14,17,18 Figure 1 shows the structures and kinome-wide profiling data generated at DiscoverX (scanMAX or KINOMEscan) for three TBK1-targeting pyrimidines. 19 The data for TBK1 inhibitors MRT67307 and BX-912 (designed for PDK1 but potent inhibitor of TBK1) is already in the literature (LINCS database).…”