Challenges and limitations of the therapeutic application of protein kinase inhibitors
| Aspect | Neurodegenerative disorders | Psychiatric disorders |
|---|---|---|
| Disease complexity | - Heterogeneity of neurodegenerative diseases (e.g., sporadic vs familial forms).- Multiple pathways contribute to disease progression, requiring combination therapies. | - Psychiatric disorders have highly complex and poorly defined molecular underpinnings.- Symptoms and etiologies overlap among disorders (e.g., bipolar disorder, schizophrenia, depression). |
| Blood-brain barrier (BBB) | - PKIs must effectively cross the BBB, which limits many candidate drugs.- Chronic neurodegenerative diseases require sustained drug delivery, raising concerns about toxicity and drug stability. | - PKIs face similar BBB challenges but are typically needed for short to intermediate-term treatments, unlike the chronic therapies required for neurodegeneration. |
| Off-target effects | - Kinases are involved in numerous signaling pathways, leading to potential toxicity from off-target inhibition (e.g., cardiovascular, immune effects). | - Psychiatric patients may be more susceptible to side effects such as mood instability or cognitive impairment due to off-target effects. |
| Patient-specific variability | - Genetic mutations (e.g., LRRK2 in Parkinson’s) exist in a subset of patients, complicating treatment generalizability. | - Lack of reliable biomarkers hampers patient stratification and target validation for kinase inhibitors. |
| Long-term safety | - Long treatment durations required for neurodegeneration amplify safety concerns (e.g., hepatotoxicity, immune suppression). | - Long-term safety studies are needed, especially for disorders requiring continuous maintenance therapy (e.g., bipolar disorder). |
PKIs: protein kinase inhibitors; LRRK2: leucine-rich repeat kinase 2