Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

Bissaro, Maicol; Federico, Stephanie; Salmaso, Veronica; Sturlese, Mattia; Spalluto, Giampiero; Moro, Stefano

doi:10.1002/cmdc.201800632

Cited by 18 publications

(13 citation statements)

References 31 publications

(62 reference statements)

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“…This event reduces the ability of SQSTM1 to eliminate the polyubiquitinated proteins by autophagy clearance creating a toxic micro-environment for the neurons and thus cell death (Lee et al, 2019). (Battaini, 2001). Regarding their implications in ALS, it was described that PKC activity was increased in ALS patients, suggesting that alterations in this kinase have effects on neuronal viability through the regulation of voltage-dependent Ca 2+ channels (Krieger, Lanius, Pelech, & Shaw, 1996).…”

Section: Protein Tyrosine Kinase 2 (Ptk2) Inhibitorsmentioning

confidence: 99%

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Palomo

Nozal

Rojas-Prats

et al. 2020

British J Pharmacology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

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Section: Protein Tyrosine Kinase 2 (Ptk2) Inhibitorsmentioning

confidence: 99%

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Palomo

Nozal

Rojas-Prats

et al. 2020

British J Pharmacology

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“…On the other hand, CK1δ has emerged as a potential target for other diseases. CK1δ inhibitors have been proposed to inhibit the phosphorylation of TDP-43, a pathological hallmark of central nervous system (CNS) diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia [33,34]. CK1δ is also a potential target for Parkinson's disease and pulmonary fibrosis [35,36].…”

Section: Aging Discussionmentioning

confidence: 99%

CK1δ as a potential therapeutic target to treat bladder cancer

Lin

Chen

Hsieh

et al. 2020

Aging

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Bladder cancer is the second most common genitourinary malignancy in the world. However, only immunecheckpoint inhibitors and erdafitinib are available to treat advanced bladder cancer. Our previous study reported that 4-((4-(4-ethylpiperazin-1-yl) phenyl)amino)-N-(3,4,5-trichlorophenyl)-7H-pyrrolo-[2, 3-d]pyrimidine-7-carboxamide hydrochloride (13i HCl) is a potent CK1δ inhibitor showing significant anti-bladder cancer activity. In this study, we elucidated the pharmacological mechanisms underlying 13i HCl's inhibition of human bladder cancer. Our results demonstrate that expression of the CSNK1D gene, which codes for CK1δ, is upregulated in superficial and infiltrating bladder cancer patients in two independent datasets. CK1δ knockdown decreased β-catenin expression in bladder cancer cells and inhibited their growth. Additionally, 13i HCl suppressed bladder cancer cell proliferation and increased apoptosis. We also observed that inhibition of CK1δ using 13i HCl or PF-670462 triggers necroptosis in bladder cancer cells. Finally, 13i HCl inhibited bladder cancer cell migration and reversed their mesenchymal characteristics. These findings suggest further development of 13i HCl as a potential therapeutic agent to treat bladder cancer is warranted.

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“…Recent studies have suggested that riluzole may exert its actions through a direct link on TDP-43 self-interaction, without change to total TDP-43 levels in neuroblastoma cells in vitro (30). Furthermore, it has been hypothesised that expression of a truncated protein kinase, CK1δ, leads to phosphorylation, mislocalisation and aggregation of TDP-43 (31), and that riluzole is may inhibit this process (10). However, in contrast to these results, we observed no alteration of TDP-43 phosphorylation nor decreases to insoluble TDP-43 with riluzole treatment, indicating that riluzole may not exert these effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, people with ALS have increased levels of the excitatory neurotransmitter glutamate in cerebrospinal fluid (CSF) (6), and altered excitability of motor neurons may be an early feature of disease (7,8). Amongst a myriad of other potential disease-relevant effects of riluzole, the drug has also been proposed to affect estradiol transport (9), to inhibit kinases potentially involved in ALS pathology (10), and to decrease activation of the heat shock response related to protein aggregation (11).…”

Section: Introductionmentioning

confidence: 99%

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis

Wright

Gatta

Shen

et al. 2019

Preprint

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease most commonly treated with riluzole, a small molecule considered to act at least in part via modulation of glutamatergic neurotransmission. However, riluzole affords only a modest extension of lifespan for people living with ALS and its precise mechanisms of action remain largely unclear. Likewise, the vast majority of ALS cases are characterised by the pathological accumulation of cytoplasmic TDP-43, but the effects of riluzole in an in vivo model of ALS with disease-reminiscent TDP-43 pathology have not been thoroughly studied. We therefore tested the effects of daily riluzole treatment on TDP-43 pathology and disease onset and progression in transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons of the brain and spinal cord (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS', mice). We found that treatment of rNLS mice with riluzole beginning from the first day of hTDP-43ΔNLS expression failed to alter disease onset, diseaseassociated weight loss or performance on multiple motor behavioural tasks over a 6week period. Riluzole treatment also did not alter soluble or insoluble TDP-43 protein levels or TDP-43 phosphorylation in rNLS mice. By quantifying levels of key proteins involved in glutamatergic signalling, we identified a dramatic loss in GluA3 protein in the rNLS mice after disease onset, however riluzole was unable to ameliorate this disease-associated molecular phenotype. Finally, we assessed the ability of riluzole to affect disease in a long-term post-disease onset study in rNLS mice, and found that riluzole similarly had no effect on progression of late-stage disease or animal survival. Together, our findings demonstrate that the rNLS mouse model recapitulates glutamatergic receptor alterations reminiscent of ALS, but the approved ALS therapeutic riluzole has no effect on disease phenotypes in these animals.These studies suggest that strategies directly targeting disease-relevant pathways, such as accumulation of TDP-43 pathology, may be needed for development of more effective ALS treatments.

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Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

Cited by 18 publications

References 31 publications

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

CK1δ as a potential therapeutic target to treat bladder cancer

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis

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