Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Benn, Caroline; Dawson, Lee A.

doi:10.3389/fnagi.2020.00242

Cited by 36 publications

(26 citation statements)

References 490 publications

(590 reference statements)

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“…PF-05251749, a Casein kinase 1 delta and epsilon (CK1δ and ε) inhibitor initially developed by Pfizer Company for AD was tested for phase-1 safety and tolerability following preclinical studies considering circadian rhythm as a major parameter for assessment. No further development was updated since October 2018, however Biogen has acquired the molecule for further studies in AD population in January 2020 (Benn & Dawson, 2020). Future research should concentrate on early intervention to reduce CK1ε/δ by understanding the prophylactic potential.…”

Section: Casein Kinase 1 (Ck1)mentioning

confidence: 99%

Molecular and Therapeutic Targets for Amyloid-beta Plaques in Alzheimer's Disease: A Review Study

Thomas

Wilson

2024

BCN

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Alzheimer’s disease (AD) is characterized by progressive loss of cognition and a gradual decrease in memory. Though AD is considered the most persistent form of dementia and a global concern, no complete cure or agents that can completely halt the progression of AD have been found. In the past years, considerable advancements in the understanding of cellular and molecular changes associated with AD has been investigated and numerous pharmacological targets have been recognized to enable drug development for the condition. Amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) are the major attributes of AD. Symptomatic relief is the only possible treatment available at present and a disease modifying drug is of utmost importance. Development of drugs that can inhibit different targets responsible for the formation of plaques is a potential area in AD research. This review is not a complete list of all possible targets for AD but serves to highlight the targets related to amyloid pathology and pathway concerned with the formation of amyloid fragments. This shall serve as a prospect in identification of amyloid plaque inhibitors and pave the strategies for newer drug treatments. Nevertheless, substantial research is done in this area but to bridle, the clinical difficulty remains a concern.

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Section: Casein Kinase 1 (Ck1)mentioning

confidence: 99%

Molecular and Therapeutic Targets for Amyloid-beta Plaques in Alzheimer's Disease: A Review Study

Thomas

Wilson

2024

BCN

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“…More recent CNS drug discovery comprising “non-traditional” neurodegenerative disease targets such as kinases have indicated that there is potential for optimism: there are now examples showing it is possible to generate molecules that fall within favourable CNS property space [ 75 ]. Few therapeutics developed against DDR targets for oncology indications have been developed with CNS penetration in mind ( Table 1 ).…”

Section: The Right Tissuementioning

confidence: 99%

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

Benn¹,

Gibson²,

Reynolds³

2021

JHD

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DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington’s disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers.

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“…Therefore, phosphorylation represents one of the most important regulatory mechanisms for cellular processes like protein synthesis, cell division or cell adhesion [ 3 , 4 ]. As a consequence, dysregulation of protein phosphorylation can be linked to the pathogenesis of various diseases, among others inflammatory, cardiovascular, and neurodegenerative diseases as well as cancer [ 5 , 6 ]. Within the past two decades, protein kinases attracted major attention as targets for inhibition mediated by small molecule inhibitors (SMIs).…”

Section: Introductionmentioning

confidence: 99%

Assessing the Inhibitory Potential of Kinase Inhibitors In Vitro: Major Pitfalls and Suggestions for Improving Comparability of Data Using CK1 Inhibitors as an Example

et al. 2021

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Phosphorylation events catalyzed by protein kinases represent one of the most prevalent as well as important regulatory posttranslational modifications, and dysregulation of protein kinases is associated with the pathogenesis of different diseases. Therefore, interest in developing potent small molecule kinase inhibitors has increased enormously within the last two decades. A critical step in the development of new inhibitors is cell-free in vitro testing with the intention to determine comparable parameters like the commonly used IC50 value. However, values described in the literature are often biased as experimental setups used for determination of kinase activity lack comparability due to different readout parameters, insufficient normalization or the sheer number of experimental approaches. Here, we would like to hold a brief for highly sensitive, radioactive-based in vitro kinase assays especially suitable for kinases exhibiting autophosphorylation activity. Therefore, we demonstrate a systematic workflow for complementing and validating results from high-throughput screening as well as increasing the comparability of enzyme-specific inhibitor parameters for radiometric as well as non-radiometric assays. Using members of the CK1 family of serine/threonine-specific protein kinases and established CK1-specific inhibitors as examples, we clearly demonstrate the power of our proposed workflow, which has the potential to support the generation of more comparable data for biological characterization of kinase inhibitors.

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Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Cited by 36 publications

References 490 publications

Molecular and Therapeutic Targets for Amyloid-beta Plaques in Alzheimer's Disease: A Review Study

Molecular and Therapeutic Targets for Amyloid-beta Plaques in Alzheimer's Disease: A Review Study

Drugging DNA Damage Repair Pathways for Trinucleotide Repeat Expansion Diseases

Assessing the Inhibitory Potential of Kinase Inhibitors In Vitro: Major Pitfalls and Suggestions for Improving Comparability of Data Using CK1 Inhibitors as an Example

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