Kinase Inhibitors: Promising Therapeutics for Neurodegenerative Diseases

The rationale for targeting kinases in central nervous system (CNS) drug discovery is based on the understanding that phosphorylation, catalyzed by kinases, plays a pivotal role in regulating many cellular processes, and that at least a number of phosphorylation processes may become aberrant in disease (Figure 1). Over the past decade, there has been an increasing interest in the therapeutic potential of brain penetrant kinase inhibitors for neurodegenerative diseases. The development of kinase inhibitors, such as glycogen synthase kinase-3β (GSK-3β) inhibitors for AD, leucine-rich repeat kinase 2 (LRRK2) inhibitors for PD, and mitogen-activated protein kinase kinase kinase kinase (MAP4K) inhibitors for ALS, has shown promise, though challenges like specificity, blood-brain barrier penetration, and drug resistance remain ^1-5.

Figure 1. Promising kinase targets and converging pathways in neurodegenerative diseases.
Figure source: https://doi.org/10.3389/fnagi.2020.00242

The Role of Kinases in Neurodegenerative Diseases

Kinases are integral to the regulation of signaling pathways in the brain, and alterations in their function are implicated in neurodegeneration. In neurodegenerative diseases, certain kinases are often overactive or overexpressed in specific brain regions. This dysregulation frequently drives the hyperphosphorylation of proteins that are prone to aggregation, such as tau in AD, α-synuclein in PD, and TDP-43 in ALS ⁶. Moreover, aberrant kinase signaling can also induce other disease-promoting phenotypes, including neuroinflammation and neuronal death. Conversely, loss-of-function in kinases has emerged as a critical genetic factor and a major contributor to the development of several neurodegenerative diseases.

The two main pathological hallmarks of AD are the extracellular amyloid beta (Aβ) plaques, which result from the accumulation of Aβ, and the intracellular neurofibrillary tangles (NFTs), composed of abnormally phosphorylated tau. Elevated GSK-3β activity is directly linked to tau hyperphosphorylation and increased production, contributing to molecular pathologies, neuronal damage, and cognitive decline in AD ^2,3. Fyn also represents a compelling therapeutic target for AD, as it is activated by Aβ through the cellular prion protein (PrPC) and also interacts with tau, uniquely bridging the two key pathologies in AD ⁷.

Pathologically, PD is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the accumulation of intracellular α-synuclein in the form of Lewy-body. Mutations in LRRK2 are the most common genetic cause of familial PD and represent a significant risk factor for sporadic PD ^4,8. Mutations in PTEN-induced kinase 1 (PINK1) are also associated with familial PD. Extensive evidence suggests that mitochondrial dysfunction is a central factor in PD pathophysiology (Figure 2). Mutations in autosomal dominant LRRK2 and autosomal recessive PINK1 are directly linked to mitochondrial dysfunction, highlighting their critical roles in the pathogenesis of PD.

Figure 2. Representative pathways of mitochondrial dysfunction implicated in the pathophysiology of PD. The listed proteins contribute pathologically to the different pathways.
Figure source: https://doi.org/10.1007/s11910-018-0829-3

ALS features gradual loss of muscle controls due to degeneration of motor neurons. MAP4K4, a member of the STE20 family, has been identified as a key regulator of motor neuron degeneration in ALS ^9,10. Inhibition of MAP4K4 can facilitate neuron survival and prevent neurite degeneration under conditions of exogenous or endogenous stress, suggesting that MAP4K4 is a druggable target for ALS therapeutics.

Development of Kinase Inhibitors for the Treatment of AD, PD, and ALS

In AD: GSK-3β inhibitors have been extensively studied. GSK-3β is involved in tau hyperphosphorylation and Aβ formation, both of which are key pathological features of AD. GSK-3β inhibitors like lithium and other small molecules have shown neuroprotective effects by reducing tau phosphorylation and Aβ levels ^3,11. Additionally, c-Jun N-terminal kinase (JNK) inhibitors are being explored for their role in preventing neuronal cell death ¹¹.

In PD: LRRK2 inhibitors are a major focus ⁸. Mutations in LRRK2 are linked to both familial and sporadic PD, and inhibiting its kinase activity has shown promise in preclinical models ^4,8. Several highly selective and potent LRRK2 inhibitors are currently in development, with some advancing to clinical trials. These inhibitors aim to reduce the pathological effects of mutated LRRK2, such as perturbed vesicular trafficking ¹².

In ALS: The development of MAP4K inhibitors has gained attention. MAP4K inhibitors, such as Prosetin, have demonstrated neuroprotective effects by protecting motor neurons from endoplasmic reticulum (ER) stress-induced apoptosis ^5,9.

Kinase Inhibitors in Preclinical and Clinical trials for Neurodegenerative Diseases

While several kinase inhibitors are in various stages of clinical trials, none have yet received FDA approval specifically for neurodegenerative diseases (Table 1) ¹³. The development of kinase inhibitors for neurodegenerative diseases has demonstrated promising potential in recent years. These compounds are designed to cross the blood-brain barrier and have shown efficacy in preclinical models, with ongoing efforts to advance them to clinical trials.

Table 1. Kinase inhibitors in preclinical and clinical trials for neurodegenerative diseases

Challenges in Developing Kinase-Targeted Drugs

Developing kinase-targeted drugs for the treatment of neurodegenerative diseases presents several unique challenges. One major issue is achieving specificity. Kinases have highly conserved ATP-binding sites, making it difficult to design inhibitors that selectively target only the desired kinase without affecting others, which can lead to off-target effects and toxicity ²⁰. Additionally, the blood-brain barrier poses a significant obstacle. It restricts the delivery of many potential therapeutic compounds to the brain, necessitating the development of drugs that can effectively cross this barrier¹. The complexity of kinase signaling networks in the brain is also a challenge, which means that inhibiting a single kinase may not be sufficient to produce a therapeutic effect. As a result, combination therapies are often required, which can complicate treatment regimens ²¹. Furthermore, the development of drug resistance is a concern, as cells can adapt to kinase inhibition through various mechanisms, including mutations and activation of alternative pathways ²². These challenges require innovative approaches in drug design, rigorous preclinical testing, and carefully designed clinical trials to develop effective and safe kinase-targeted therapies for neurodegenerative diseases.

Solutions for Kinase Drug Discovery and Neuroscience Research

To support neurodegenerative disease research and kinase inhibitor discovery, SignalChem Biotech (part of Sino Biological) offers comprehensive solutions. SignalChem Biotech is deeply engaged in every crucial aspect of kinase drug discovery by offering the world’s largest portfolio of highly active kinases (700+ wild-type and 400+ mutant kinases), custom enzyme and assay development, and swift compound screening and profiling services. Additionally, SignalChem Biotech has developed an extensive range of therapeutic targets for neurodegenerative diseases, such as the world’s largest recombinant tau protein library, and a plethora of signaling proteins, based on proprietary production and quality control platforms.

Discover our integrated solutions for CNS research and drug discovery.

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