Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

Łukasik, Paweł; Baranowska-Bosiacka, Irena; Kulczycka, Katarzyna; Gutowska, Izabela

doi:10.3390/ijms22062806

Cited by 49 publications

(34 citation statements)

References 138 publications

(70 reference statements)

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“…These analyses highlighted that an inhibitor for CDK2 requires a bulkier ring to be attached to the main scaffold (the pyran ring in the present case) through a flexible chain of two to three atoms. Furthermore, it should be present at the periphery of the molecule to penetrate well inside the ATP binding site to establish lipophilic and mild polar interactions [ 69 ]. In addition, docking analyses indicated that H-bond donors or acceptors on the central scaffold could substantially enhance binding with the receptor.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

et al. 2022

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Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC50 values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC50 values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

et al. 2022

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“…Recent developments in the field of small-molecule inhibitors of CDKs have led to several compounds with anticancer potencies both in vitro and in vivo and models of cancer. However, the specificity of the inhibitors, which inhibit close isoforms, is not fully achieved yet, especially for CDK5, which is involved in neurodegenerative diseases ( Łukasik et al, 2021 ). Other specific inhibitors have been developed with improved therapeutic effects, some of which are non-ATP competitive inhibitors that are selective and significantly less toxic than others like L803-mts as well as TDZD-8, VP0.7 ( Kaidanovich-Beilin et al, 2004 ; Kaidanovich-Beilin and Eldar-Finkelman, 2006 ).…”

Section: Post-translational Modifications In Alzheimer’s Diseasementioning

confidence: 99%

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

Mumtaz

Ayaz

Khan

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD.

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“…These drugs have using for the treatment of postmenopausal women with HR-positive, HER2-negative advanced, or metastatic breast cancer. The action mechanism is that inhibiting the phosphorylation of Rb protein in the G1 phase results in cell cycle arrest [127]. Palbociclib has a synergistic effect in combination therapy with either letrozole or fulvestrant [128].…”

Section: Cyclin-dependent Kinase (Cdk) Inhibitorsmentioning

confidence: 99%

The Role of Kinase Inhibitors in Cancer Therapies

Kursunluoglu¹,

Erdogan²,

Cagatay³

et al. 2021

Protein Kinases - Promising Targets for Anticancer Drug Research

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Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail.

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Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

Cited by 49 publications

References 138 publications

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

The Role of Kinase Inhibitors in Cancer Therapies

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