c-Abl Inhibitor Research Articles

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in invitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Glutamate Receptors and C-ABL Inhibitors: A New Therapeutic Approach for Parkinson's Disease.

Parkinson's disease (PD) is the second-most prevalent central nervous system (CNS) neurodegenerative condition. Over the past few decades, suppression of BCR-Abelson tyrosine kinase (c-Abl), which serves as a marker of -synuclein aggregation and oxidative stress, has shown promise as a potential therapy target in PD. c-Abl inhibition has the potential to provide neuroprotection against PD, as shown by experimental results and the first-in-human trial, which supports the strategy in bigger clinical trials. Furthermore, glutamate receptors have also been proposed as potential therapeutic targets for the treatment of PD since they facilitate and regulate synaptic neurotransmission throughout the basal ganglia motor system. It has been noticed that pharmacological manipulation of the receptors can change normal as well as abnormal neurotransmission in the Parkinsonian brain. The review study contributes to a comprehensive understanding of the approach toward the role of c-Abl and glutamate receptors in Parkinson's disease by highlighting the significance and urgent necessity to investigate new pharmacotherapeutic targets. The article covers an extensive insight into the concept of targeting, pathophysiology, and c-Abl interaction with α-synuclein, parkin, and cyclin-dependent kinase 5 (Cdk5). Furthermore, the concepts of Nmethyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) receptor, and glutamate receptors are discussed briefly. Conclusion: This review article focuses on in-depth literature findings supported by an evidence-based discussion on pre-clinical trials and clinical trials related to c-Abl and glutamate receptors that act as potential therapeutic targets for PD.

Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice

Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.

The identification of c-Abl inhibitors as potential agents for Parkinson's disease: a preliminary in silico approach.

Parkinson's disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were - 11.8kcal/mol, - 11.8kcal/mol, and - 10.8kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski's rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.

C-Abl Phosphorylates MFN2 to Regulate Mitochondrial Morphology in Cells under Endoplasmic Reticulum and Oxidative Stress, Impacting Cell Survival and Neurodegeneration.

The endoplasmic reticulum is a subcellular organelle key in the control of synthesis, folding, and sorting of proteins. Under endoplasmic reticulum stress, an adaptative unfolded protein response is activated; however, if this activation is prolonged, cells can undergo cell death, in part due to oxidative stress and mitochondrial fragmentation. Here, we report that endoplasmic reticulum stress activates c-Abl tyrosine kinase, inducing its translocation to mitochondria. We found that endoplasmic reticulum stress-activated c-Abl interacts with and phosphorylates the mitochondrial fusion protein MFN2, resulting in mitochondrial fragmentation and apoptosis. Moreover, the pharmacological or genetic inhibition of c-Abl prevents MFN2 phosphorylation, mitochondrial fragmentation, and apoptosis in cells under endoplasmic reticulum stress. Finally, in the amyotrophic lateral sclerosis mouse model, where endoplasmic reticulum and oxidative stress has been linked to neuronal cell death, we demonstrated that the administration of c-Abl inhibitor neurotinib delays the onset of symptoms. Our results uncovered a function of c-Abl in the crosstalk between endoplasmic reticulum stress and mitochondrial dynamics via MFN2 phosphorylation.

Discovery of conformationally constrained c-Abl inhibitors with potential neuroprotective effects against Parkinson’s disease

Abelson tyrosine kinase (c-Abl) is involved in various biological processes in neurodegenerative diseases and is an attractive target for anti-PD (Parkinson's disease) drug discovery. Based on our previous work, we designed several novel c-Abl inhibitors through a conformational constrained strategy and evaluated their pharmacological activities. Among them, compound A6 exhibited superior inhibitory activity against c-Abl than nilotinib in the homogenous time-resolved fluorescence (HTRF) assay. Furthermore, A6 displayed higher neuroprotective effects against SH-SY5Y cell death induced by MPP+ and lower cytotoxicity than that of nilotinib. Molecular modeling revealed that the 1H-pyrrolo[2,3-B]pyridine ring may contribute to the high affinity of A6 for binding to c-Abl. Collectively, these results suggest that A6 deserves further investigation as a c-Abl inhibitor for neurodegenerative disorders.

Development of 18F-Labeled PET Tracer Candidates for Imaging of the Abelson Non-receptor Tyrosine Kinase in Parkinson's Disease.

Activated Abelson non-receptor tyrosine kinase (c-Abl) plays a harmful role in neurodegenerative conditions such as Parkinson's disease (PD). Inhibition of c-Abl is reported to have a neuroprotective effect and be a promising therapeutic strategy for PD. We have previously identified a series of benzo[d]thiazole derivatives as selective c-Abl inhibitors from which one compound showed high therapeutic potential. Herein, we report the development of a complementary positron emission tomography (PET) tracer. In total, three PET tracer candidates were developed and eventually radiolabeled with fluorine-18 for in vivo evaluation studies in mice. Candidate [18F]3 was identified as the most promising compound, since it showed sufficient brain uptake, good washout kinetics, and satisfactory metabolic stability. In conclusion, we believe this tracer provides a good starting point to further validate and explore c-Abl as a target for therapeutic strategies against PD supported by PET.

Vodobatinib, a potent, orally bioavailable brain-penetrating inhibitor of c-Abl as a potential neuroprotective agent for treatment of Parkinson disease

Vodobatinib, a potent, orally bioavailable brain-penetrating inhibitor of c-Abl as a potential neuroprotective agent for treatment of Parkinson disease

C-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease.

Growing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD. We used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow. We found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus. Our results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies.

The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

Plasma and cerebrospinal fluid pharmacokinetics of vodobatinib, a neuroprotective c-Abl tyrosine kinase inhibitor for the treatment of Parkinson's disease

BackgroundPreclinical evidence suggests that c-Abl is critical in the pathogenesis of Parkinson's Disease (PD). Vodobatinib (K0706) is a potent, specific Abl kinase inhibitor currently being developed for the treatment of PD. In previously reported studies, nilotinib, a multikinase c-Abl inhibitor, did not show clinical activity as evidenced by no improvement of symptoms or the rate of decline after one to six months of treatment at the maximum permissible dose, presumably because of insufficient CNS penetration. Here we report clinical PK and safety data for vodobatinib. ObjectivesTo determine safety, plasma PK, and CSF penetration of vodobatinib in healthy volunteers and PD subjects following oral administration, and compare CSF levels to in vitro concentrations required for c-Abl inhibition relative to data reported for nilotinib. MethodsInhibition of c-Abl kinase activity and c-Abl binding affinity were first assessed in vitro. Healthy human volunteers and PD patients received various oral doses of vodobatinib once-daily for seven and fourteen days respectively, to assess safety, and plasma and CSF PK. ResultsIn in vitro assays, vodobatinib was more potent (kinase IC50 = 0.9 nM) than nilotinib (kinase IC50 = 15–45 nM). Administration of vodobatinib 48, 192 and 384 mg to healthy subjects for 7 days yielded mean Cmax, CSF values of 1.8, 11.6, and 12.2 nM respectively, with the two highest doses exceeding the IC50 over the entire dosing interval. Cavg, CSF values were 6–8 times greater than the IC50. Comparable CSF levels were observed in PD patients. All doses were well tolerated in both cohorts. ConclusionBased on achieved CSF concentrations, the potential for c-Abl inhibition in the brain is substantially higher with vodobatinib than with nilotinib. The CSF PK profile of vodobatinib is suitable for determining if c-Abl inhibition will be neuroprotective in PD patients.

Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.

Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.

Discovery of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as C-Abl inhibitors with potential neuroprotective effect

C-Abl is involved in various biological processes and plays an important role in neurodegenerative diseases, especially Parkinson's disease (PD). Previous studies have found that nilotinib shows a neuroprotective effect in cell and animal models of PD by inhibiting the activation of c-Abl. But the low blood–brain barrier permeability and potential toxicity limit the further use of nilotinib in PD. Based on molecular modeling studies, a series of 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives were designed and synthesized. In particular, compound 9a exhibited significant inhibitory activity against c-Abl and a potent neuroprotective effect against MPP+-induced SH-SY5Y cell death. Moreover, 9a not only displayed lower cell toxicity compared with nilotinib, but also showed higher oral bioavailability and proper permeability of the blood–brain barrier. This paper provides 4-methyl-3-(pyridin-2-ylamino)benzamide derivatives as a new scaffold for c-Abl inhibitor with potential neuroprotective effect.

C-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease.

Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.

Bisphenol A induces apoptosis in response to DNA damage through c-Abl/YAPY357/ p73 pathway in P19 embryonal carcinoma stem cells

Bisphenol A (2,2-bis(4′-hydroxyphenyl) propane, BPA) is a well-known endocrine-disrupting compound that is widely used in various daily products and exhibits embryonic development toxicity and genotoxicity. However, the affected signaling pathways involved in embryonic development especially the interactions of involved proteins remain unclear. In our previous study (Ge et al., 2021), BPA induces DNA damage and apoptosis in Xenopus embryos, resulting in multiple malformations of larvae. However, the signaling pathways induced for apoptosis response to DNA damage are still not well elucidated. Here, we systematically elucidated the enriched pathways affected by BPA and illustrated the interactions of involved proteins. Results indicated that BPA affected multiple embryonic development pathways including Hippo, TGF-β, Wnt, and Notch pathways. Furthermore, the protein-protein interaction network suggested that the c-Abl/YAPY357/p73 pathway may play a key role in apoptosis induction in response to DNA damage. P19 embryonal carcinoma stem cells, as a developmental toxicity model, were treated with different BPA concentrations to establish an in vitro model to verify the role of the c-Abl/YAPY357/p73 pathway in apoptosis. BPA triggered DNA damage and significantly upregulated the expression levels of c-Abl, phosphorylated YAPY357, phosphorylated p73Y99, and cleaved caspase-3 protein (p < 0.05), thus decreasing cell viability and transcriptionally activating the p73 target genes Bax and Puma. These data suggested that BPA activated the c-Abl/YAPY357/p73 pathway in response to DNA damage. Imatinib, an inhibitor of tyrosine kinase c-Abl, significantly downregulated the elevated expression levels of p-YAPY357, p-p73Y99 and cleaved caspase-3 (p < 0.05) caused by BPA and then ameliorated the cell index of P19 cells in the BPA-treated group. Therefore, this substance restrained the phosphokinase activity of c-Abl and suppressed the c-Abl/YAPY357/p73 pathway. Results showed that the c-Abl/YAPY357/p73 pathway served as a mechanism for caspase-3 activation that induced the apoptosis response to DNA damage stress.

C-Abl-induced Olig2 phosphorylation regulates the proliferation of oligodendrocyte precursor cells.

Oligodendrocytes (OLs), the myelinating cells in the central nervous system (CNS), are differentiated from OL progenitor cells (OPCs). The proliferation of existing OPCs is indispensable for myelination during CNS development and remyelination in response to demyelination stimulation. The transcription factor Olig2 is required for the specification of OLs and is expressed in the OL lineage. However, the post-translational modification of Olig2 in the proliferation of OPCs is poorly understood. Herein, we identified that c-Abl directly phosphorylates Olig2 mainly at the Tyr137 site, and that Olig2 phosphorylation is essential for OPC proliferation. The expression levels of c-Abl gradually decreased with brain development; moreover, c-Abl was highly expressed in OPCs. OL-specific c-Abl knockout at the developmental stage led to an insufficient proliferation of OPCs, a decreased expression of myelin-related genes, and myelination retardation. Accordingly, a c-Abl-specific kinase inhibitor suppressed OPC proliferation in vitro. Furthermore, we observed that OL-specific c-Abl knockout reduced OPC proliferation and remyelination in a cuprizone model of demyelination. In addition, we found that nilotinib, a clinically used c-Abl inhibitor, decreased the expression of myelin basic protein (Mbp) and motor coordination in mice, indicating a neurological side effect of a long-term administration of the c-Abl inhibitor. Thus, we identified the important role of c-Abl in OLs during developmental myelination and remyelination in a disease model.

High-Performance Extended-Gate Field-Effect Transistor for Kinase Sensing in Aβ Accumulation of Alzheimer’s Disease

An amyloid-beta peptide (Aβ) is generally believed to be a pathological marker of Alzheimer's disease (AD), but it is still of great significance to explore the upstream and downstream relationship of Aβ in AD. It is previously reported that c-Abl, a nonreceptor tyrosine kinase, can be activated by Aβ, but the interaction between Aβ and c-Abl is still unknown. Herein, an extended-gate field-effect transistor (EG-FET)-based sensor has been developed to monitor the level of c-Abl with high sensitivity and selectivity. Our peptide-functionalized EG-FET sensor as the signal transducer can follow c-Abl activity with electron transfer by its specific phosphorylation. The sensor presents a good linear correlation over c-Abl concentrations of 1 pg/mL to 3.05 μg/mL. The sensor was successfully applied to quantify c-Abl activity in the brain tissue of AD transgenic mice, and the interaction between c-Abl and Aβ in AD mice was explored by administering the c-Abl inhibitor (imatinib) and the agonist (DPH). Our work is expected to provide an important reference for early diagnosis and treatment of AD.

Endothelin-1 Induced Phosphorylation of Caveolin-1 and Smad2C in Human Vascular Smooth Muscle Cells: Role of NADPH Oxidases, c-Abl, and Caveolae Integrity in TGF-β Receptor Transactivation.

Caveolin-1(Cav-1) is one of the most important components of caveolae in the cell membrane, which plays an important role in cell signaling transduction, such as EGFR and TGF-β receptor transactivation. The purpose of this study was to evaluate the effect of c-Abl and NAD(P)H oxidases (NOX) on phosphorylation of Cav-1 and consequently their effect on phosphorylation of Smad2C induced by Endothelin-1 in human vascular smooth muscle cells (VSMCs). In this study, all experiments were performed using human VSMCs. The phosphorylation level of the Caveolin-1 and Smad2C proteins were assessed by western blotting using Phospho-Caveolin-1 (Tyr14) antibody and phospho-Smad2 (Ser465/467) antibody. The data were reported as mean ± SEM. The VSMCs treated with endothelin-1(ET-1) (100 nanomolar (nmol)) demonstrated a time-dependent increase in the pCav-1 level (p<0.05). The inhibitors of NOX (diphenyleneiodonium) (p<0.05), cholesterol depleting agent (beta-cyclodextrin) (p<0.05) and c-Abl inhibitor (PP1) (p<0.01) were able to reduce the level of the phospho-Cav-1 and phospho-Smad2C induced by Et-1 (p<0.05). Our results proposed that caveolae structure, NOX, c-Abl played an important role in the phosphorylation of Cav-1 induced by ET-1 in the human VSMCs. Furthermore, our findings showed that phosphoCav-1 involved in TGFR transactivation. Thus, Et-1 via a transactivation-dependent mechanism can cause phosphorylation of Smad2C.

Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity.

ABSTRACTParkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5 000 000 cases worldwide. Historically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, PD pathology is now known to be widespread and to affect serotonin, cholinergic and norepinephrine neurons as well as nerve cells in the olfactory system, cerebral hemisphere, brain stem, spinal cord, and peripheral autonomic nervous system. PD pathology is characterized by the accumulation of misfolded α‐synuclein, which is thought to play a critical role in the etiopathogenesis of the disease. Animal models of PD suggest that activation of the Abelson tyrosine kinase (c‐Abl) plays an essential role in the initiation and progression of α‐synuclein pathology and neurodegeneration. These studies demonstrate that internalization of misfolded α‐synuclein activates c‐Abl, which phosphorylates α‐synuclein and promotes α‐synuclein pathology within the affected neurons. Additionally, c‐Abl inactivates parkin, disrupting mitochondrial quality control and biogenesis, promoting neurodegeneration. Post‐mortem studies of PD patients demonstrate increased levels of tyrosine phosphorylated α‐synuclein, consistent with the activation of c‐Abl in human disease. Although the c‐Abl inhibitor nilotinib failed to demonstrate clinical benefit in two double‐blind trials, novel c‐Abl inhibitors have been developed that accumulate in the brain and may inhibit c‐Abl at saturating levels. These novel inhibitors have demonstrated benefits in animal models of PD and have now entered clinical development. Here, we review the role of c‐Abl in the neurodegenerative disease process and consider the translational potential of c‐Abl inhibitors from model studies to disease‐modifying therapies for Parkinson's disease. © 2021 Inhibikase Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway.

Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.