Anti-cancer Dynamics of Natural Phytochemical Inhibitors of Cyclin-Dependent Kinases

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

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Advances in Pyrazole Based Scaffold as Cyclin-Dependent Kinase 2 Inhibitors for the Treatment of Cancer

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666211027104957 ◽

2021 ◽

Vol 21 ◽

Author(s):

Jahara Shaikh ◽

Kavitkumar Patel ◽

Tabassum Khan

Keyword(s):

Cell Cycle ◽

Proliferative Activity ◽

Docking Studies ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinases ◽

Ic50 Value ◽

Anti Cancer ◽

Specific Cancer ◽

Cell Cycle Deregulation

: The transformation of a normal cell into a tumor cell is one of the initial steps in cell cycle deregulation. The cell cycle is regulated by cyclin-dependent kinases (CDKs) that belong to the protein kinase family. CDK2 is an enchanting target for specific genotypes tumors since cyclin E is selective for CDK2 and the deregulation of specific cancer forms. Thus, CDKs inhibitor specifically CDK2/cyclin A-E has the potential to be a valid cancer target as per the currently undergoing clinical trials. Mostly pyrazole scaffolds have shown selectivity and potency for CDK2 inhibitors. This review demonstrates pyrazole and pyrazole fused with other heterocyclic rings for anti-proliferative activity. Based on the in vitro and molecular docking studies, the IC50 value of various hybrids is revealed to display the most potent analogs for CDK2 inhibition. Thus, the review emphasizes various lead analogs of pyrazole hybrids which can be found to be very potent and selective for anti-cancer drugs.

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Coming Full Circle: Cyclin-Dependent Kinases as Anti-cancer Drug Targets

Subcellular Biochemistry - Genome Stability and Human Diseases ◽

10.1007/978-90-481-3471-7_1 ◽

2009 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Robert P. Fisher

Keyword(s):

Drug Targets ◽

Cancer Drug ◽

Cyclin Dependent Kinases ◽

Full Circle ◽

Anti Cancer

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Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells

10.1101/2020.06.05.135715 ◽

2020 ◽

Author(s):

Boshi Wang ◽

Simone Brandenburg ◽

Alejandra Hernandez-Segura ◽

Thijmen van Vliet ◽

Elisabeth M. Jongbloed ◽

...

Keyword(s):

Transcriptional Activity ◽

Malignant Cells ◽

Cancer Treatments ◽

Cyclin Dependent Kinases ◽

Anti Cancer ◽

Genes Encoding ◽

Secretory Phenotype ◽

Stable Growth ◽

Suppressive Mechanism

AbstractCellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Several anti-cancer interventions function partly by inducing malignant cells into senescence. However, because of systemic administration and lack of specificity, anti-cancer treatments are associated with premature senescence of various non-malignant cells. Therapy-induced non-malignant senescent cells can have profound detrimental pro-tumorigenic and pro-disease functions via activation of a pro-inflammatory and NF-κB-mediated secretory phenotype (SASP). Inhibitors of the cyclin-dependent kinases 4/6 (CDK4/6i) has recently shown to have potent cytostatic effects with reduced toxicities. Here, we show that CDK4/6i lead non-malignant cells to a senescent state that lacks the pro-inflammatory and NF-κB-associated SASP. Interestingly, CDK4/6i-induced senescence overexpressed a number of genes encoding for secreted proteins, which we show being dependent on p53 transcriptional activity. CDK4/6i-induced p16+ senescent cells with a p53-associated (PASP), but not NF-κB-associated (NASP), secretory phenotype do not exert detrimental and pro-tumorigenic functions, but still retain the capacity to induce paracrine senescence and undergo clearance in vivo. Our data suggest that that senescent cells with a PASP but without a NASP may be well-tolerated and may represent a less toxic outcome for cancer interventions.

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