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Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism: the cell cycle. This cycle is primarily regulated by cyclin-dependent kinase (CDK)-cyclin complexes, checkpoint kinases, and CDK inhibitors. Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as single-agent therapy and in combination with traditional cytotoxic or molecular targeting agents. In this review, we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development, including both pan-CDK inhibitors and CDK4/6-selective inhibitors. In addition, we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

Previous research has indicated that the currently available histone deacetylase inhibitors (HDACis) are not effective as monotherapies against oral squamous cell carcinoma (OSCC). However, HDACis act synergistically with other therapeutic agents to exert significant antitumor activities. Thus, a strategy to develop chemotherapeutic agents by combining several active groups based on histone deacetylase (HDAC) into a single molecule as a conjugate that modulates multiple cellular pathways may be useful for the treatment of OSCC. The novel inhibitor Roxyl-ZR was prepared by organic synthesis and its anticancer effects on OSCC were investigated by cell metabolism (n=5), colony formation (n=3), cell cycle (n=3), cell apoptosis (n=3), wound healing (n=3), transwell migration (n=3), and 5-bromo-2'-deoxyuridine staining (n=3) assays in vitro and in in vivo xenograft mice models (4 mice/group for subcutaneous xenograft and 3 mice/group for orthotopic xenograft ). The abundance of Ki67, Bcl-2, and p-STAT3 was detected by immunohistochemistry staining (n=4). Apoptotic cells in the tumor tissues of mice were detected by terminal deoxynucleotidyl transferase dUTP nickend labeling assay (n=3). The abundance of related proteins levels were evaluated by western blot (n=3). E-cadherin expression was detected by an immunofluorescence assay (n=3). Compared with the approved HDACi, conjugated Roxyl-ZR exhibited significantly higher antitumor effects in OSCC cells. Roxyl-ZR suppressed OSCC cell proliferation by inducing the reduction of S phase and inducing caspase-dependent apoptosis by down-regulating Bcl-2 expression. Moreover, Roxyl-ZR attenuated the epithelial-mesenchymal transition, which is closely associated with migration and invasion. In addition, Roxyl-ZR inhibited OSCC xenograft mice models and showed low toxicity. The mechanism underlying the Roxyl-ZR-enhanced sensitivity to HDACi may be attributed to the inhibition of key regulators of JAK1-STAT3 signaling pathway. HDAC-cyclin-dependent kinase conjugates represent a novel approach to the development of OSCC treatment. Our findings may open a new avenue for the development of novel inhibitors for the treatment of OSCC.

Cyclin-dependent kinases (CDKs) orchestrate cell cycle progression through precise temporal control of substrate phosphorylation. While traditional biochemical approaches and phosphoproteomics have provided valuable insights into CDK-mediated regulation, these methods require cell population analyses and cannot capture real-time dynamics in individual cells. The recent development of fluorescent biosensors has revolutionized our ability to monitor CDK activity in living cells with unprecedented temporal and spatial resolution. Here, we comprehensively review genetically encoded fluorescent biosensors for measuring CDK activity. The two major modes of action in CDK activity biosensors—FRET-based and translocation-based biosensors—enable researchers to select appropriate tools for their specific experimental objectives. These biosensors have revealed precise spatiotemporal CDK activity dynamics across diverse model systems, including yeast, cultured mammalian cells, worms, flies, frog egg extract, fish, and mice. Such technological advances are transforming our understanding of quantitative principles underlying cell cycle control and opening new avenues for investigating cell cycle regulation in various biological contexts.Key words: CDK, FRET, cell cycle, live imaging, biosensor

The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine–threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.

Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism： the cell cycle. This cycle is primarily regulated by cyclin-dependent kinase （CDK）-cyclin complexes, checkpoint kinases, and CDK inhibitors. Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as singleagent therapy and in combination with traditional cytotoxic or molecular targeting agents. In this review, we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development, including both pan-CDK inhibitors and CDK4/6-selective inhibitors. In addition, we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.

In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.

The mammalian cell cycle is precisely controlled by cyclin-dependent kinases (CDKs) and related pathways such as the RB and p53 pathways. Recent research on long non-coding RNAs (lncRNAs) indicates that many lncRNAs are involved in the regulation of critical cell cycle regulators such as the cyclins, CDKs, CDK inhibitors, pRB, and p53. These lncRNAs act as epigenetic regulators, transcription factor regulators, post-transcription regulators, and protein scaffolds. These cell cycle-regulated lncRNAs mainly control cellular levels of cell cycle regulators via various mechanisms, and may provide diversity and reliability to the general cell cycle. Interestingly, several lncRNAs are induced by DNA damage and participate in cell cycle arrest or induction of apoptosis as DNA damage responses. Therefore, deregulations of these cell cycle regulatory lncRNAs may be involved in tumorigenesis, and they are novel candidate molecular targets for cancer therapy and diagnosis.

Long non-coding RNAs (lncRNAs) are non-coding RNAs (ncRNAs) longer than 200nt. They have complex biological functions and take part in multiple fundamental biological processes, such as cell proliferation, differentiation, survival and apoptosis. Recent studies suggest that lncRNAs modulate critical regulatory proteins involved in cancer cell cycle, such as cyclin, cell cycle protein-dependent kinases (CDK) and cell cycle protein-dependent kinase inhibitors (CKI) through different mechanisms. To clarify the role of lncRNAs in the regulation of cell cycle will provide new ideas for design of antitumor therapies which intervene with the cell cycle progression. In this paper, we review the recent studies about the controlling of lncRNAs on cell cycle related proteins such as cyclin, CDK and CKI in different cancers. We further outline the different mechanisms involved in this regulation and describe the emerging role of cell cycle-related lncRNAs in cancer diagnosis and therapy.

A major characteristic of cancer is dysregulated cell division, which results in aberrant growth of cells. Consequently, medicinal targets that prevent cell division would be useful in the fight against cancer. The primary regulator of proliferation is a complex consisting of cyclin and cyclin-dependent kinases (CDKs). The FDA has granted approval for CDK inhibitors (CDKIs) to treat metastatic hormone receptor-positive breast cancer. Specifically, CDK4/6 CDKIs block the enzyme activity of CDK4 and CDK6. Unfortunately, the majority of first-generation CDK inhibitors, also known as pan-CDK inhibitors because they target multiple CDKs, have not been authorized for clinical use owing to their serious side effects and lack of selection. In contrast to this, significant advancements have been created to permit the use of pan-CDK inhibitors in therapeutic settings. Notably, the toxicity and negative consequences of pan-CDK inhibitors have been lessened in recent years thanks to the emergence of combination therapy tactics. Therefore, pan-CDK inhibitors have renewed promise for clinical use when used in a combination regimen. The members of the CDK family have been reviewed and their primary roles in cell cycle regulation were covered in this review. Next, we provided an overview of the state of studies on CDK inhibitors.