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Protein kinases have essential responsibilities in controlling several cellular processes, and their abnormal regulation is strongly related to the development of cancer. The implementation of protein kinase inhibitors has significantly transformed cancer therapy by modifying treatment strategies. These inhibitors have received substantial FDA clearance in recent decades. Protein kinases have emerged as primary objectives for therapeutic interventions, particularly in the context of cancer treatment. At present, 69 therapeutics have been approved by the FDA that target approximately 24 protein kinases, which are specifically prescribed for the treatment of neoplastic illnesses. These novel agents specifically inhibit certain protein kinases, such as receptor protein-tyrosine kinases, protein-serine/threonine kinases, dual-specificity kinases, nonreceptor protein-tyrosine kinases, and receptor protein-tyrosine kinases. This review presents a comprehensive overview of novel targets of kinase inhibitors, with a specific focus on cyclin-dependent kinases (CDKs) and epidermal growth factor receptor (EGFR). The majority of the reviewed studies commenced with an assessment of cancer cell lines and concluded with a comprehensive biological evaluation of individual kinase targets. The reviewed articles provide detailed information on the structural features of potent anticancer agents and their specific activity, which refers to their ability to selectively inhibit cancer-promoting kinases including CDKs and EGFR. Additionally, the latest FDA-approved anticancer agents targeting these enzymes were highlighted accordingly. [ABSTRACT FROM AUTHOR]

Main conclusion: Excess of KRP4 in the developing kernels in rice causes poor filling of the grains possibly through inhibition of CDKA;2 and CDKB;1 activity mediated by its interaction with CDKF;3. The potential yield of the rice varieties producing compact and heavy panicles bearing numerous spikelets is compromised because a high percentage of spikelets remain poorly filled, reportedly because of a high expression of KRPs that causes suppression of endosperm cell proliferation. To test the stated negative relationship between KRP expression and grain filling, Orysa;KRP4 was overexpressed under the control of seed-specific glutelin promoter in IR-64 rice variety that shows good grain filling. The transgenic lines showed more than 15-fold increase in expression of KRP4 in the spikelets concomitant with nearly 50% reduction in grain filling compared with the wild type without producing any significant changes on the other yield-related parameters like panicle length and the spikelets numbers that were respectively 30.23 ± 0.89 cm and 229.25 ± 33.72 per panicle in the wild type, suggesting a highly organ-targeted effect of the genetic transformation. Yeast two-hybrid test revealed CDKF;3 as the interacting partner of KRP4, and CDKF;3 was found to interact with CDKA;2, CDKB;1 and CDKD;1. Significant decrease in grain filling in the transgenic lines compared with the wild type due to overexpression of KRP4 could be because of suppression of the activity of CDKB;1 and CDKA;2 by inhibition of their phosphorylation directly by CDKF;3, or mediated through inhibition of phosphorylation of CDKD;1 by CDKF;3. The study thus indicated that suppression of expression of KRP(s) by genetic manipulation of their promoters could be an important way of improving the yield of the rice varieties bearing compact and heavy panicles. [ABSTRACT FROM AUTHOR]

Summary CDKs are the master regulator of cell division and their activity is controlled by the regulatory subunit cyclins and phosphorylation by the CAKs. However, the role of MAP kinases in regulating plant cell cycle or CDKs have not been explored. Here, we report that the MAP kinases OsMPK3, OsMPK4, and OsMPK6 physically interact and phosphorylate OsCDKD and its regulatory subunit OsCYCH in rice. MAP kinases phosphorylate CDKD at Ser‐168 and Thr‐235 residues in OsCDKD. The MAP kinase‐mediated phosphorylation of OsCDKD is required for its activation to control the small RNA biogenesis. The phosphodead version of OsCDKD fails to activate the C‐terminal domain of RNA Polymerase II, thereby negatively impacting small RNA transcription. Further, the overexpression lines of wild‐type (WT) OsCDKD and phosphomimic OsCDKD show increased root growth, plant height, tiller number, panicle number, and seed number in comparison to WT, phosphodead OsCDKD‐OE, and kinase‐dead OsCDKD‐OE plants. In a nutshell, our study establishes a novel regulation of OsCDKD by MAPK‐mediated phosphorylation in rice. The phosphorylation of OsCDKD by MAPKs imparts a positive effect on rice growth and development by regulating miRNAs transcription. [ABSTRACT FROM AUTHOR]

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy. Schematic illustration of preparation and CCLM-targeted therapy of engineered cell membrane-camouflaged nanodrug. (A) Preparation of engineered cell membrane-camouflaged nanoparticles co-delivered with CDK inhibitor (CDKi) and anti-mouse/human programmed death ligand 1 antibody (aPD-L1) in response to extracellular acidity of tumor microenvironment. (B) Multifunctional nanodrug targets CDKs in colon cancer cell and tumor-associated myeloid cell (TAMC) to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Dormancy release and reactivation in temperate trees are mainly controlled by temperature and are affected by age, but the underlying molecular mechanisms are still unclear. In this study, we explored the effects of low temperatures in winter and warm temperatures in spring on dormancy release and reactivation in Larix kaempferi. Further, we established the relationships between cell-cycle genes and cambium cell division. The results showed that chilling accelerated L. kaempferi bud break overall, and the longer the duration of chilling is, the shorter the bud break time is. After dormancy release, warm temperatures induced cell-cycle gene expression; when the configuration value of the cell-cycle genes reached 4.97, the cambium cells divided and L. kaempferi reactivated. This study helps to predict the impact of climate change on wood production and provides technical support for seedling cultivation in greenhouses. [ABSTRACT FROM AUTHOR]

Protein kinases have essential responsibilities in controlling several cellular processes, and their abnormal regulation is strongly related to the development of cancer. The implementation of protein kinase inhibitors has significantly transformed cancer therapy by modifying treatment strategies. These inhibitors have received substantial FDA clearance in recent decades. Protein kinases have emerged as primary objectives for therapeutic interventions, particularly in the context of cancer treatment. At present, 69 therapeutics have been approved by the FDA that target approximately 24 protein kinases, which are specifically prescribed for the treatment of neoplastic illnesses. These novel agents specifically inhibit certain protein kinases, such as receptor protein-tyrosine kinases, protein-serine/threonine kinases, dual-specificity kinases, nonreceptor protein-tyrosine kinases, and receptor protein-tyrosine kinases. This review presents a comprehensive overview of novel targets of kinase inhibitors, with a specific focus on cyclin-dependent kinases (CDKs) and epidermal growth factor receptor (EGFR). The majority of the reviewed studies commenced with an assessment of cancer cell lines and concluded with a comprehensive biological evaluation of individual kinase targets. The reviewed articles provide detailed information on the structural features of potent anticancer agents and their specific activity, which refers to their ability to selectively inhibit cancer-promoting kinases including CDKs and EGFR. Additionally, the latest FDA-approved anticancer agents targeting these enzymes were highlighted accordingly.

Osteocytes have recently been identified as a new regulator of bone remodeling, but the detailed mechanism of their differentiation from osteoblasts remains unclear. The purpose of this study is to identify cell cycle regulators involved in the differentiation of osteoblasts into osteocytes and determine their physiological significance. The study uses IDG‐SW3 cells as a model for the differentiation from osteoblasts to osteocytes. Among the major cyclin‐dependent kinases (Cdks), Cdk1 is most abundantly expressed in IDG‐SW3 cells, and its expression is down‐regulated during differentiation into osteocytes. Inhibition of CDK1 activity reduces IDG‐SW3 cell proliferation and differentiation into osteocytes. Osteocyte and Osteoblast‐specific Cdk1 knockout in mice (Dmp1‐Cdk1KO) results in trabecular bone loss. Pthlh expression increases during differentiation, but inhibiting CDK1 activity reduces Pthlh expression. Parathyroid hormone‐related protein concentration is reduced in the bone marrow of Dmp1‐Cdk1KO mice. Four weeks of Parathyroid hormone administration partially recovers the trabecular bone loss in Dmp1‐Cdk1KO mice. These results demonstrate that Cdk1 plays an essential role in the differentiation from osteoblast to osteocyte and the acquisition and maintenance of bone mass. The findings contribute to a better understanding of the mechanisms of bone mass regulation and can help develop efficient therapeutic strategies for osteoporosis treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disorder that affects different regions of the brain. Its pathophysiology includes the accumulation of β-amyloid protein, formation of neurofibrillary tangles, and inflammatory processes. Genetic factors are involved in the onset of AD, but they are not fully elucidated. Identification of gene expression in encephalic tissues of patients with AD may help elucidate its development. Our objectives were to characterize and compare the gene expression of CDK10, CDK11, FOXO1, and FOXO3 in encephalic tissue samples from AD patients and elderly controls, from the auditory cortex and cerebellum. RT-qPCR was used on samples from 82 individuals (45 with AD and 37 controls). We observed a statistically significant increase in CDK10 (p = 0.029*) and CDK11 (p = 0.048*) gene expression in the AD group compared to the control, which was most evident in the cerebellum. Furthermore, the Spearman test demonstrated the presence of a positive correlation of gene expression both in the auditory cortex in the AD group (r = 0.046/p = 0.004) and control group (r = 0.454/p = 0.005); and in the cerebellum in the AD group (r = 0.654 /p < 0.001). There was no statistically significant difference and correlation in the gene expression of FOXO1 and FOXO3 in the AD group and the control. In conclusion, CDK10 and CDK11 have high expression in AD patients compared to control, and they present a positive correlation of gene expression in the analyzed groups and tissues, which suggests that they play an important role in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Dormancy release and reactivation in temperate trees are mainly controlled by temperature and are affected by age, but the underlying molecular mechanisms are still unclear. In this study, we explored the effects of low temperatures in winter and warm temperatures in spring on dormancy release and reactivation in Larix kaempferi. Further, we established the relationships between cell-cycle genes and cambium cell division. The results showed that chilling accelerated L. kaempferi bud break overall, and the longer the duration of chilling is, the shorter the bud break time is. After dormancy release, warm temperatures induced cell-cycle gene expression; when the configuration value of the cell-cycle genes reached 4.97, the cambium cells divided and L. kaempferi reactivated. This study helps to predict the impact of climate change on wood production and provides technical support for seedling cultivation in greenhouses.

Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM. [ABSTRACT FROM AUTHOR]

Alt-EJ is an error-prone DNA double-strand break (DSBs) repair pathway coming to the fore when first-line repair pathways, c-NHEJ and HR, are defective or fail. It is thought to benefit from DNA end-resection—a process whereby 3′ single-stranded DNA-tails are generated—initiated by the CtIP/MRE11-RAD50-NBS1 (MRN) complex and extended by EXO1 or the BLM/DNA2 complex. The connection between alt-EJ and resection remains incompletely characterized. Alt-EJ depends on the cell cycle phase, is at maximum in G2-phase, substantially reduced in G1-phase and almost undetectable in quiescent, G0-phase cells. The mechanism underpinning this regulation remains uncharacterized. Here, we compare alt-EJ in G1- and G0-phase cells exposed to ionizing radiation (IR) and identify CtIP-dependent resection as the key regulator. Low levels of CtIP in G1-phase cells allow modest resection and alt-EJ, as compared to G2-phase cells. Strikingly, CtIP is undetectable in G0-phase cells owing to APC/C-mediated degradation. The suppression of CtIP degradation with bortezomib or CDH1-depletion rescues CtIP and alt-EJ in G0-phase cells. CtIP activation in G0-phase cells also requires CDK-dependent phosphorylation by any available CDK but is restricted to CDK4/6 at the early stages of the normal cell cycle. We suggest that suppression of mutagenic alt-EJ in G0-phase is a mechanism by which cells of higher eukaryotes maintain genomic stability in a large fraction of non-cycling cells in their organisms. [ABSTRACT FROM AUTHOR]

The current study continues the evaluation of the anticancer potential of three de novo synthesized pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulfonamides—MM129, MM130, and MM131—against human cancer cells of HeLa, HCT 116, PC-3, and BxPC-3 lines. The pro-apoptotic activity of the investigated sulfonamides was shown by observations of changes in the mitochondrial transmembrane potential of the tested cells, externalization of phosphatidylserine on the cellular membrane surface, and cell morphology in microscopic imaging. The computational studies have shown that MM129 exhibited the lowest binding energy values when docked against CDK enzymes. In addition, the highest stability was shown for complexes formed between MM129 and CDK5/8 enzymes. All examined compounds induced cell cycle arrest in the G0/G1 phase in the BxPC-3 and PC-3 cells and simultaneously caused the accumulation of cells in the S phase in the HCT 116 cells. In addition, the increase in the subG1 fraction was observed in PC-3 and HeLa cells. The application of a fluorescent H2DCFDA probe revealed the high pro-oxidative properties of the tested triazine derivatives, especially MM131. In conclusion, the obtained results suggest that MM129, MM130, and MM131 exhibited strong pro-apoptotic properties towards investigated cells, mainly against the HeLa and HCT 116 cell lines, and high pro-oxidative potential as well. Moreover, it is suggested that the anticancer activity of the tested compounds may be associated with their ability to inhibit CDK enzymes activities. [ABSTRACT FROM AUTHOR]

Cancer is considered one of the most lethal diseases responsible for causing deaths worldwide. Although there have been many breakthroughs in anticancer development, cancer remains the major cause of death globally. In this regard, targeting cancer-causing enzymes is one of the efficient therapeutic strategies. Biological functions like cell cycle, transcription, metabolism, apoptosis, and other depend primarily on cyclin-dependent kinases (CDKs). These enzymes help in the replication of DNA in the normal cell cycle process, and deregulation in the functioning of any CDK can cause abnormal cell growth, which leads to cancer. This review is focused on anticancer drug discovery against cell cycle CDK enzyme using an in silico technique, i.e., molecular docking studies. Molecular docking helps in deciphering the key interactions formed within the inhibitor and the respective enzyme. This concise study provides an overview of the most current in silico research advancements made in the field of anticancer drug discovery. The findings presented in the current review article can help in understanding the nature of inhibitor-target interactions and provide information on the structural and molecular prerequisites for the inhibition of cell cycle CDKs. [ABSTRACT FROM AUTHOR]

Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials against a wide range of cancers. Flavopiridol was recently approved as an orphan drug for chronic lymphocytic leukemia treatment. In this study, we report the isolation and characterization of rohitukine from the bark of D. binectariferum. Further, rohitukine was estimated across the Western-Ghats and the North-East regions of India. Additionally, D. binectariferum is also reported (∼45 compounds) to produce many natural derivatives of rohitukine and terpenoids, which were investigated in-silico to reveal promising CDK inhibitors. The metabolite fingerprinting of tissues of D. binectariferum was studied using HPTLC and FTIR. The distribution of major chromone alkaloid rohitukine was estimated by HPLC. Further, the pharmacological potential of D. binectariferum compounds was evaluated in-silico by discovering the potential protein targets, molecular docking, ADMET analysis and MD simulation. The isolation of rohitukine has yielded 0.6% from the bark of D. binectariferum. A higher percent of rohitukine was found in the Jog populations (0.58% & 1.28%: leaf & bark), whereas least was observed in the Phasighat population (∼0.06%: both leaf & bark). Across the geographic regions, a higher percent of rohitukine was found in the Central-southern Western Ghats, whereas lower in the northern parts of the Western Ghats and Northeast regions. The leaves produce a considerably higher percent of rohitukine and could be used as a sustainable source of rohitukine. The rohitukine analogues, along with other chromone alkaloids of D. binecatariferum were found to be more interactive with the “kinases” family of proteins, majorly “Serine/threonine-protein kinase PFTAIRE-2” (CDK15) with high confidence level (0.94–0.98). The molecular docking of these chromone alkaloids found a strong binding energy with six CDKs (−3.1 to −10.6 kcal/mol) along with a promising ADMET profile. In addition, molecular dynamic simulation found that the rohitukine complexes are virtually constant with CDK-1, 2, 9 and 15, which is substantiated with MM-PBSA free energy calculations. The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.

Combination of cyclin‐dependent kinases (CDKs) and histone deacetylases (HDACs) inhibitors may have statistical synergy in suppressing cancer cell proliferation. Herein, a novel CDKs/HDACs dual inhibitor T‐17 was rationally designed, synthesized, and evaluated. Our results demonstrated that T‐17 concurrently exhibited potent and balanced inhibitory activity against CDKs (IC50 = 18.0 nM) and HDACs (IC50 = 6.6 nM) and also displayed good cell viability inhibitory effect on four cancer cell lines. Meanwhile, T‐17 blocked the MDA‐MB‐231 and A549 cell cycle at G1 phase and S phase, respectively. In addition, T‐17 induced MDA‐MB‐231 cells apoptosis and inhibited the HDACs and CDKs mediated signaling pathways. Finally, we also found that T‐17 had good antitumor activity in vivo. In summary, these results indicated that T‐17 would be a promising lead compound which deserves further research. [ABSTRACT FROM AUTHOR]

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3 , featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC 50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML. [Display omitted] • • C3 degrades CDK2 with DC 50 value of 18.73 ± 10.78 nM, and D max of 86.83 ± 8.75 %. • • C3 notably reduced the protein levels of CDK4/6/9 and FLT3 in AML cell lines. • • The pro-differentiation effect of C3 was 72.77 ± 3.51 % at 6.25 nM on day 5. • • C3 exhibited anti-proliferative activity in MV4-11 with IC 50 = 2.90 ± 0.14 nM. [ABSTRACT FROM AUTHOR]

Dysregulation of cyclin-dependent kinases (CDKs) impacts cell proliferation, driving cancer. Here, we ask why the cyclin-D/CDK4 complex governs cell cycle progression through the longer G1 phase, whereas cyclin-E/CDK2 regulates the shorter G1/S phase transition. We consider available experimental cellular and structural data including cyclin-E's high-level burst, sustained duration of elevated cyclin-D expression, and explicit solvent molecular dynamics simulations of the inactive monomeric and complexed states, to establish the conformational tendencies along the landscape of the distinct activation scenarios of cyclin-D/CDK4 and cyclin-E/CDK2 in the G1 phase and G1/S transition of the cell cycle, respectively. These lead us to propose slower activation of cyclin-D/CDK4 and rapid activation of cyclin-E/CDK2. We provide the mechanisms through which this occurs, offering innovative CDK4 drug design considerations. Our insightful mechanistic work addresses a compelling cell cycle regulation question and illuminates the distinct activation speeds between the G1 and the G1/S phases, which are crucial for function. [Display omitted] • Cyclin-D/CDK4 activation is slower than cyclin-E/CDK2, informing cancer drug design • There are distinct activation speeds for G1 phase and G1/S transition • Conformational dynamics of CDKs inform novel therapeutic strategies • Study bridges cell cycle regulation with CDK activation mechanisms Zhang et al. discover different activation speeds of cyclin-D/CDK4 and cyclin-E/CDK2, crucial for the timescales of the cell cycle progression stages. These findings suggest harnessing the differential speeds' mechanisms in cancer drug development, collectively providing a deeper understanding of cell cycle regulation and opening new pathways for targeted drug discovery. [ABSTRACT FROM AUTHOR]

Objective: We investigated the expression of CDKs and prognosis in breast cancer. Materials and Methods: The Oncomine database examined CDK gene expressions in breast cancer. The prescient worth of CDKs in bosom malignant growth patients was analyzed utilizing the Kaplan-Meier Plotter. The expression changes of CDKs in tumor staging were analyzed in the GEPIA database. The role of CDKs in DNA replication and the cell cycle was analyzed utilizing the KEGG data set. Using the CBioPortal database, the association between CDKs gene expression and CDKs in breast cancer was investigated. The Encori database was used to study miRNAs that target CDKs. Results: Oncomine data showed that the expressions of CDK1, CDK5 and CDK20 in breast cancer patients were upregulated, while mRNA expression levels in CDK2 and CDK6 decreased, and CDK3, CDK4 and CDK7~19 were not expression data. Results from the GEPIA database revealed that the expression levels of CDK1, CDK2, CDK4, CDK5, CDK7, CDK8, and CDK20 were greater in breast cancer tissues than in normal tissues, and that CDK1 and CDK5 were significantly different, and the expression levels of CDK3 and CDK1 in the former were lower than those in the latter, while those in the latter did not change. Kaplan-Meier Plotter data showed that CDK1, CDK3, CDK4 and CDK20 were associated with a dismal prognosis in individuals with breast cancer, while mRNA level in CDK8 was associated with progression after survival. Conclusions: CDK1, CDK2c, CDK4, CDK5, CDK7, CDK8 and CDK20 can be used as molecular markers for breast cancer patients, or as potential targets for breast cancer therapy by targeting CDKs.

How eukaryotic cells control their duplication is a fascinating example of how a biological system self-organizes specific activities to temporally order cellular events. During cell cycle progression, the cellular level of CDK (Cyclin-Dependent Kinase) activity temporally orders the different cell cycle phases, ensuring that DNA replication occurs prior to segregation into two daughter cells. CDK activity requires the binding of a regulatory subunit (cyclin) to the core kinase, and both CDKs and cyclins are well conserved throughout evolution from yeast to humans. As key regulators, they coordinate cell cycle progression with metabolism, DNA damage, and cell differentiation. In meiosis, the special cell division that ensures the transmission of genetic information from one generation to the next, cyclins and CDKs have acquired novel functions to coordinate meiosis-specific events such as chromosome architecture, recombination, and synapsis. Interestingly, meiosis-specific cyclins and CDKs are common in evolution, some cyclins seem to have evolved to acquire CDK-independent functions, and even some CDKs associate with a non-cyclin partner. We will review the functions of these key regulators in meiosis where variation has specially flourished.

Circular RNAs (circRNAs) participate in the occurrence and development of various diseases through different mechanisms, such as by acting as a microRNA (miRNA) sponge, interacting with RNA-binding proteins, and regulating gene transcription and protein translation. For example, the abnormal expression of specific circRNAs in tumor cells can alter key regulatory factors and the cell cycle network, resulting in cell cycle disorders and the development and metastasis of tumors. Here, we summarize the mechanisms involved in the circRNA-mediated processes that lead to uncontrolled cell cycle and tumor cell proliferation. Extensive studies investigating the abnormal expression of circRNAs in different cancer types have been conducted. The unique characteristics of circRNAs and their ability to regulate the cell cycle through diverse mechanisms is extremely valuable in tumor diagnosis, treatment, and prognosis. Our review may assist in further understanding the circRNA-mediated regulation of the cell cycle in tumors and provide insights for research on circRNA-based therapeutic strategies and biological diagnosis for cancer. [ABSTRACT FROM AUTHOR]

ThezincfingerproteinGrowthFactor Independence1 (GFI1) actsasatranscriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasiansand15%in acutemyeloidleukemia (AML)patients, hencemostprobably predisposing to AML. One reason for this is that GFI1-36N differs from thewildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine Nmethyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be amarker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib. [ABSTRACT FROM AUTHOR]

Okazaki fragment maturation (OFM) stands as a pivotal DNA metabolic process, crucial for genome integrity and cell viability. Dysregulation of OFM leads to DNA single-strand breaks- accumulation, which is linked to various human diseases such as cancer and neurodegenerative disorders. Recent studies have implicated LIG3-XRCC1 acting in an alternative OFM pathway to the canonical FEN1-LIG1 pathway. Here, we reveal that polynucleotide kinase-phosphatase (PNKP) is another key participant in DNA replication, akin to LIG3-XRCC1. Through functional experiments, we demonstrate PNKP's enrichment at DNA replication forks and its association with PCNA, indicating its involvement in replication processes. Cellular depletion of PNKP mirrors defects observed in OFM-related proteins, highlighting its significance in replication fork dynamics. Additionally, we identify PNKP as a substrate for cyclin-dependent kinase 1/2 (CDK1/2), which phosphorylates PNKP at multiple residues. Mutation analysis of these phosphorylation sites underscores the importance of CDK2-mediated PNKP phosphorylation in DNA replication. Our findings collectively indicate a novel role for PNKP in facilitating Okazaki fragment joining, thus shedding light on its contribution to genome stability maintenance., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cyclins along with their catalytic units, Cyclin-dependent kinases (CDKs) regulate the cell cycle transition and transcription; and are essentially known as 'master regulators' in modulating DNA damage response (DDR) and replication stress. In addition to influencing DNA repair and damage signaling, CDKs also play a pivotal role in cell division fidelity and the maintenance of genomic integrity after DNA damage. In this review, we focus on the intricate ways by which specific CDKs mainly CDK7, CDK9, and CDK12/13, regulate the cell cycle progression and transcription and how their modulation can lead to lethal effects on the integrity of the genome. With a better knowledge of how these CDKs control the DDR and replication stress, it is now possible to combine CDK inhibitors with chemotherapeutic drugs that damage DNA in ways that can be applied in clinical settings as successful therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.

Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM.

Simple Summary: By combining drug screens, transcriptomic studies, and in vitro assays, our study identified the natural product toyocamycin as a potent and selective CDK9 inhibitor. Thus, toyocamycin can be used as a new small molecule to modulate CDK9 activity in preclinical research. Through docking simulations, we identified its specific binding sites, which could spark some interest to design novel small molecule CDK9 inhibitors. Aberrant transcription in cancer cells involves the silencing of tumor suppressor genes (TSGs) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA-hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSGs. To discover novel drugs that trigger TSG reactivation in cancer cells, we used a GFP-reporter system whose expression is silenced by promoter DNA hypermethylation and histone deacetylation. After screening a natural product drug library, we identified that toyocamycin, an adenosine-analog, induces potent GFP reactivation and loss of clonogenicity in human colon cancer cells. Connectivity-mapping analysis revealed that toyocamycin produces a pharmacological signature mimicking cyclin-dependent kinase (CDK) inhibitors. RNA-sequencing revealed that the toyocamycin transcriptomic signature resembles that of a specific CDK9 inhibitor (HH1). Specific inhibition of RNA Pol II phosphorylation level and kinase assays confirmed that toyocamycin specifically inhibits CDK9 (IC50 = 79 nM) with a greater efficacy than other CDKs (IC50 values between 0.67 and 15 µM). Molecular docking showed that toyocamycin efficiently binds the CDK9 catalytic site in a conformation that differs from other CDKs, explained by the binding contribution of specific amino acids within the catalytic pocket and protein backbone. Altogether, we demonstrated that toyocamycin exhibits specific CDK9 inhibition in cancer cells, highlighting its potential for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Cyclin‐dependent kinases (CDKs) are protein kinases that play a key role in cell division and transcriptional regulation. Recent studies have demonstrated the critical roles of CDKs in various viral infections. However, the molecular processes underpinning CDKs' roles in viral infection and host antiviral defense are unknown. This minireview briefly overviews CDKs' functions and highlights the most recent discoveries of CDKs' emerging roles during viral infections, thereby providing a scientific and theoretical foundation for antiviral regulation and shedding light on developing novel drug targets and therapeutic strategies against viral infection. [ABSTRACT FROM AUTHOR]

More than 20 members of the human cyclin‐dependent kinases (CDKs) family share the feature of being activated by cyclins. CDKs have been involved in diverse biological processes, such as cell cycle, transcription, DNA damage response, and apoptosis. If CDKs are not properly regulated, they can cause diseases like cancer. CDKs are Ser/Thr kinases that work with cyclins to control cell cycle progression. Various CDK‐cyclin complexes phosphorylate particular target proteins and drive different cell cycle stages. Accumulating evidence demonstrated that CDKs play an essential role in the cell cycle; however, their roles in antiviral innate immunity are just emerging. This minireview summarizes how CDKs play their roles in antiviral innate immunity. Our goal is to draw attention to the involvement of CDKs in antiviral innate immunity, whether as separate entities or as components of CDK/cyclin complexes that have gotten less attention in the past. HIGHLIGHTS: 1.Cyclin‐dependent kinases (CDKs) participate in the Toll‐like receptors signaling pathways and regulate antiviral innate immunity2.CDKs are involved in the nuclear factor kappa B signaling pathway to regulation antiviral innate immunity3.CDKs are involved in antiviral innate immunity by regulating the Janus kinase‐signal transducers and activators of transcription signaling pathway [ABSTRACT FROM AUTHOR]

BACKGROUND: Globally, breast cancer (BC) has become one of the most prevalent malignancies and the leading cause of tumor-related deaths among women. Dysregulation of the cell cycle is a well-known hallmark of cancer development and metastasis. CDKs are essential components of the cell-cycle regulatory system with aberrant expression in a variety of cancers, including BC. In the development of targeted cancer treatment, reestablishing the regulation of the cell cycle by modulation of CDKs has emerged as a promising approach. METHODS: Herein, we used a bioinformatic approach to assess the expression pattern, prognostic and diagnostic importance, and clinical relevance of CDKs in BC. Additionally, we conducted a functional enrichment analysis of deregulated CDKs using the STRING and KEGG databases to delineate the role of CDKs in breast tumorigenesis. RESULTS: Gene expression analysis revealed substantial deregulation of CDKs in BC, with CDK1, CDK11A, and CDK18 showing a fold change of > ± 1.5. Also, metastatic tumors showed high expression of CDK1 in the single cell RNA sequencing analysis of primary and metastatic breast tumors. Additionally, it was found that dysregulated CDK expression affects overall survival (OS) and relapse-free survival (RFS) of BC patients. CONCLUSION: The study's multimodal analytical methodologies imply that modulating CDKs for BC treatment is a promising approach. [ABSTRACT FROM AUTHOR]

Abstract Extensive studies in the past 30 years have established that cyclin-dependent kinases (CDKs) exert many diverse, important functions in a number of molecular and cellular processes that are at play during development. Not surprisingly, mutations affecting CDKs or their activating cyclin subunits have been involved in a variety of rare human developmental disorders. These recent findings are reviewed herein, giving a particular attention to the discovered mutations and their demonstrated or hypothesized functional consequences, which can account for pathological human phenotypes. The review highlights novel, important CDK or cyclin functions that were unveiled by their association with human disorders, and it discusses the shortcomings of mouse models to reveal some of these functions. It explains how human genetics can be used in combination with proteome-scale interaction databases to loom regulatory networks around CDKs and cyclins. Finally, it advocates the use of these networks to profile pathogenic CDK or cyclin variants, in order to gain knowledge on protein function and on pathogenic mechanisms.

With a high occurrence rate and high mortality, the treatment of colorectal cancer (CRC) is increasingly attracting the attention of scholars. Hub genes that determine the phenotypes of CRC become essential for targeted therapy. In the present study, the importance of cyclin-dependent kinases (CDKs) on the occurrence of CRC was identified by data mining of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The results showed that the gene expression levels of CDK1, CDK4, and CDK6 were obviously changed in different stages of CRC. Among the CDKs, CDK4 was suggested as an independent risk factor for CRC based on Cox analysis. Furthermore, chondroitin sulfate (CS), a kind of dietary supplement to treat osteoarthritis, was predicted to treat CRC based on its chemical structure and GEO datasets. Cell assay experiments with the human CRC cell line HCT-116 also verified this prediction. CS inhibited the gene and protein expression levels of CDKs and increased the ratios of apoptotic or dead HCT-116 cells by regulating mitogen-activated protein (MAP) kinase pathways. Our data highlight the essential roles of CDKs in CRC carcinogenesis and the effects of CS on treating CRC, both of which will contribute to the future CRC treatment. [ABSTRACT FROM AUTHOR]

The cyclin-dependent kinase inhibitor p21 plays a critical role in regulating cell cycle and cell proliferation. We previously cloned the dog p21 gene and found that unlike human p21, dog p21 is expressed as 2 isoforms due to the proline-directed phosphorylation at serine 123 (S123). Here, we identified that PPM1D, also called Wip1 and a Mg(2+)-dependent phosphatase, dephosphorylates dog p21 protein at serine 123. Specifically, we showed that the level of S123-phosphorylated dog p21 is increased by a PPM1D inhibitor in a dose-dependent manner. We also showed that over-expression of PPM1D decreases, whereas knockdown of PPM1D increases, the level of S123-phosphorylated dog p21 regardless of p53. Additionally, in vitro phosphatase assay was performed and showed that phosphorylated S123 in dog p21 is dephosphorylated by recombinant rPPM1D, which contains the catalytic domain of human PPM1D (residue 1-420), but not by the phosphatase dead rPPM1D (D314A). Furthermore, dephosphorylation of S123 by rPPM1D can be abrogated by PPM1D inhibitor or by withdrawal of Mg(2+). Finally, we showed that upon PPM1D inhibition, the level of S123-phosphorylated dog p21 was increased, concomitantly with decreased expression of cyclin A, cyclin B, Rb, and PCNA. Together, our results indicate that PPM1D functions as a phosphatase of dog p21 at serine 123 and plays a role in cell cycle control via p21.

With a high occurrence rate and high mortality, the treatment of colorectal cancer (CRC) is increasingly attracting the attention of scholars. Hub genes that determine the phenotypes of CRC become essential for targeted therapy. In the present study, the importance of cyclin-dependent kinases (CDKs) on the occurrence of CRC was identified by data mining of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The results showed that the gene expression levels of CDK1, CDK4, and CDK6 were obviously changed in different stages of CRC. Among the CDKs, CDK4 was suggested as an independent risk factor for CRC based on Cox analysis. Furthermore, chondroitin sulfate (CS), a kind of dietary supplement to treat osteoarthritis, was predicted to treat CRC based on its chemical structure and GEO datasets. Cell assay experiments with the human CRC cell line HCT-116 also verified this prediction. CS inhibited the gene and protein expression levels of CDKs and increased the ratios of apoptotic or dead HCT-116 cells by regulating mitogen-activated protein (MAP) kinase pathways. Our data highlight the essential roles of CDKs in CRC carcinogenesis and the effects of CS on treating CRC, both of which will contribute to the future CRC treatment.

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.

Catalysis using supported gold nanoparticles has attracted significant research interest due to their unique properties and potential that is directly related to their particle size. An efficient one-pot, three-component procedure is developed for the preparation of pyrimido[4,5- b ][1,6]naphthyridin-4(1H)-one derivatives (4a–h) by cyclocondensation of 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (1), aromatic aldehydes (2), and 1-benzylpiperidin-4-one (3) in the presence of zeolite-nano Au as a green catalyst in ethanol at 80 °C. The presented methodology has a number of advantages including a reusable catalyst, easy access, short reaction times, high yields, and an easy work-up. The nanogold catalyst is characterized by X-ray diffraction and transmission electron microscopy. The structures of the prepared compounds are established by elemental analyses and spectral data (infrared, mass spectrometry, 1H, and 13C NMR). While molecular docking studies show that products 4a and 4c have binding affinities with the active site of CDKs. A bio-evaluation assay revealed that some of the products exhibit strong to moderate effects against proliferation of Huh7 in an in vitro model of human liver cancer cells as confirmed by morphological alteration. Compounds 4c and 4a offer the lowest IC50 values at 22.5 and 39 µM, respectively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cell proliferation during seed germination is determinant for an appropriate seedling establishment. The present work aimed to evaluate the participation of two maize B-type Cyclins during germination and under the stimulus of two simple sugars: sucrose and glucose. We found out that the corresponding genes, ZmCycB1;2 and ZmCycB2;1, increased their expression at 24 h of germination, but only ZmCycB1;2 responded negatively to sugar type at the highest sugar concentration tested (120 mM). Also, CycB1;2 showed differential protein levels along germination in response to sugar, or its absence. Both CycBs interacted with CDKA;1 and CDKB1;1 by pull down assays. By an immunoprecipitation approach, it was found that each CycB associated with two CDKB isoforms (34 and 36 kDa). A higher proportion of CycB1;2-CDKB-36kDa was coincident to an increased kinase activity in the presence of sugar and particularly in glucose treatment at 36 h of imbibition. CycB1;2-CDKB activity increased in parallel to germination advance and this was dependent on sugar: glucose > sucrose > No sugar treatment. At RAM, CycB1;2 was more abundant in nuclei on Glucose at late germination; DNA-CycB1;2 colocalization was parallel to CycB1;2 inside the nucleus. Overall, results point out CycB1;2 as a player on promoting proliferation during germination by binding a specific CDKB isoform partner and changing its cellular localization to nuclei, co-localizing with DNA, being glucose a triggering signal. • CycBs protein patterns are differentially modified by sugars along germination. • CycB1; 2 and 2;1 form active complexes with CDKB1;1 during maize germination. • Glucose promoted CycB1;2 localization in the nucleus at late germination in RAM. [ABSTRACT FROM AUTHOR]

Rice being a staple crop for human, its production is required to be increased significantly, particularly keeping in view the expected world's population of 9.6 billion by the year 2050. In this context, although the rice breeding programs have been successful in increasing the number of spikelets per panicle, the basal spikelets remain poorly filled, undermining the yield potential. The present study also found the grain filling to bear negative correlation with the panicle grain density. The poorly filled basal spikelets of the compact-panicle cultivars showed a lower endosperm cell division rate and ploidy status of the endosperm nuclei coupled with no significant greater expression of CYCB;1 and CYCH;1 compared with the apical spikelets, unlike that observed in the lax-panicle cultivars, which might have prevented them from overcoming apical dominance. Significantly greater expression of CYCB2;2 in the basal spikelets than in the apical spikelets might also have prevented the former to enter into endoreduplication. Furthermore, expression studies of KRPs in the caryopses revealed that a higher expression of KRP;1 and KRP;4 in the basal spikelets than in the apical spikelets of the compact-panicle cultivars could also be detrimental to grain filling in the former, as KRPs form complex primarily with CDKA-CYCD that promotes S-phase activity and G1/S transition, and thus inhibits endosperm cell division. The study indicates that targeted manipulation of expression of CYCB1;1, CYCB2;2, CYCH1;1, KRP;1 and KRP4 in the basal spikelets of the compact-panicle cultivars may significantly improve their yield performance. [ABSTRACT FROM AUTHOR]

Long‐term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non‐small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO2) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA‐mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes. [ABSTRACT FROM AUTHOR]

Structure-based pharmacophore mapping, drug-likeness and ADMET profiles were used as tools in our virtual screening process, in addition to molecular docking studies that were used to find novel CDK4/6 inhibitors with different heterocyclic scaffolds, having appropriate physicochemical parameters and non toxic. Aim of this work is to search for new promising CDK4/6 inhibitors, that have a great potential to be approved as clinically useful drugs in cancer therapy. Six promising hits were retrieved after applying virtual screening filters, these hits were subjected to molecular docking studies and were compared with the approved CDK4/6 inhibitor drug (palbociclib). Finally, we can conclude that they have a great potential to target CDK4/6 in a closely similar manner as palbociclib, in addition to their predicted good ADMET properties, they can be considered as novel hopeful leads for CDK4/6 inhibition and deserve further clinical investigations. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases (CDKs) play an important role in the regulation of cell proliferation, and many CDK inhibitors were developed. However, pan-CDK inhibitors failed to be approved due to intolerant toxicity or low efficacy and the use of selective CDK4/6 inhibitors is limited by resistance. Protein degraders have the potential to increase selectivity, efficacy and overcome resistance, which provides a novel strategy for regulating CDKs. In this review, we summarized the function of CDKs in regulating the cell cycle and transcription, and introduced the representative CDK inhibitors. Then we made a detailed introduction about four types of CDKs degraders, including their action mechanisms, research status and application prospects, which could help the development of novel CDKs degraders.

Targeting cyclin‐dependent kinases (CDKs) is a promising method of therapy for cancer. Unfortunately, the efficacy of CDK inhibitors in hepatocellular carcinoma (HCC) is limited, due in part to incomplete understanding of cell cycle progression and a lack of specific biomarkers to adequately identify which patients may be responsive to CDK inhibitors. In the present study, we report that microtubule‐associated protein RP/EB family member 1 (MAPRE1), a gene involved in cell cycle and microtubule regulation, is significantly increased in HCC tissue, promotes HCC cell proliferation, enhances in vitro tumorigenesis, and associates with poor prognosis of HCC. We demonstrate that MAPRE1 binds with CDK2, resulting in the hyperphosphorylation of the CDK2 Thr161 residue in HCC cells. Our findings reveal that targeting MAPRE1 might be an effective therapeutic strategy in HCC, and suggest that MAPRE1 expression might provide a promising biomarker to stratify patients with HCC who may benefit from treatment with CDK inhibitors. [ABSTRACT FROM AUTHOR]