Novel Medicinal Chemistry Strategies Targeting CDK5 for Drug Discovery

Tang, Wen; Lin, Caiyu; Yu, Quanwei; Zhang, Dan; Liu, Yun; Zhang, Lele; Zhou, Zhilan; Zhang, Jifa; Ouyang, Liang

doi:10.1021/acs.jmedchem.3c00566

Cited by 10 publications

(3 citation statements)

References 156 publications

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“…The resultant hyperactivation and mislocalization of CDK5 lead to the hyperphosphorylation of its substrates. CDK5 phosphorylates Tau, which is a crucial substrate of CDK5, and causes it to disassociate from microtubules, self-aggregate, and eventually form PHFs and insoluble NFTs in neurons [61][62][63][64][65].…”

Section: Cdk5 Inhibitorsmentioning

confidence: 99%

Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics

Singh,

Ansari,

Mahmood

et al. 2024

Horm Metab Res

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Alzheimer’s disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: β-amyloid (Aβ) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aβ plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aβ, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aβ-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3β and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

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Section: Cdk5 Inhibitorsmentioning

confidence: 99%

Targeting Abnormal Tau Phosphorylation for Alzheimer’s Therapeutics

Singh,

Ansari,

Mahmood

et al. 2024

Horm Metab Res

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“…Despite the extensive studies that correlating CDK5 expression and cancer occurrence, drug therapies that selectively inhibit CDK5 were not available until very recently [22]. Selective targeting of CDK5 is extremely difficult due to the high degree of similarity with other CDKs [23].…”

Section: Introductionmentioning

confidence: 99%

“…Selective targeting of CDK5 is extremely difficult due to the high degree of similarity with other CDKs [23]. Pan CDK inhibitors remain the chief therapeutic option for the treatment of CDK5-related illnesses [22]. First-generation pan CDK inhibitors, Roscovitine and flavopiridol, have entered Phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations

Shoaib,

Almogaddam,

Andijani

et al. 2023

Metabolites

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Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial−mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics–generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

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