Insights into the structural and functional activities of forgotten Kinases: PCTAIREs CDKs.

In cells, signal transduction heavily relies on the intricate regulation of protein kinases, which provide the fundamental framework for modulating most signaling pathways. Dysregulation of kinase activity has been implicated in numerous pathological conditions, particularly in cancer. The druggable nature of most kinases positions them into a focal point during the process of drug development. However, a significant challenge persists, as the role and biological function of nearly one third of human kinases remains largely unknown.Within this diverse landscape, cyclin-dependent kinases (CDKs) emerge as an intriguing molecular subgroup. In human, this kinase family encompasses 21 members, involved in several key biological processes. Remarkably, 13 of these CDKs belong to the category of understudied kinases, and only 5 having undergone broad investigation to date. This knowledge gap underscores the pressing need to delve into the study of these kinases, starting with a comprehensive review of the less-explored ones.Here, we will focus on the PCTAIRE subfamily of CDKs, which includes CDK16, CDK17, and CDK18, arguably among the most understudied CDKs members. To contextualize PCTAIREs within the spectrum of human pathophysiology, we conducted an exhaustive review of the existing literature and examined available databases. This approach resulted in an articulate depiction of these PCTAIREs, encompassing their expression patterns, 3D configurations, mechanisms of activation, and potential functions in normal tissues and in cancer.We propose that this effort offers the possibility of identifying promising areas of future research that extend from basic research to potential clinical and therapeutic applications.

Cyclin-dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple-negative breast cancer by affecting the immune microenvironment.

BACKGROUND: Clinical studies on programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors for treating triple-negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor-infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin-dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies. METHODS: The authors tested three CDK inhibitors on the TNBC cell lines MDA-MB-231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune-related mechanisms of different combination therapy experiments in a 4T1 cell-transplanted BALB/c mouse model. RESULTS: Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell-cycle arrest and induced apoptosis in human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD-L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels. CONCLUSIONS: Combination therapy with CDK and PD-L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

Loss of fragile WWOX gene leads to senescence escape and genome instability.

Induction of DNA damage response (DDR) to ensure accurate duplication of genetic information is crucial for maintaining genome integrity during DNA replication. Cellular senescence is a DDR mechanism that prevents the proliferation of cells with damaged DNA to avoid mitotic anomalies and inheritance of the damage over cell generations. Human WWOX gene resides within a common fragile site FRA16D that is preferentially prone to form breaks on metaphase chromosome upon replication stress. We report here that primary Wwox knockout (Wwox-/-) mouse embryonic fibroblasts (MEFs) and WWOX-knockdown human dermal fibroblasts failed to undergo replication-induced cellular senescence after multiple passages in vitro. Strikingly, by greater than 20 passages, accelerated cell cycle progression and increased apoptosis occurred in these late-passage Wwox-/- MEFs. These cells exhibited γH2AX upregulation and microsatellite instability, indicating massive accumulation of nuclear DNA lesions. Ultraviolet radiation-induced premature senescence was also blocked by WWOX knockdown in human HEK293T cells. Mechanistically, overproduction of cytosolic reactive oxygen species caused p16Ink4a promoter hypermethylation, aberrant p53/p21Cip1/Waf1 signaling axis and accelerated p27Kip1 protein degradation, thereby leading to the failure of senescence induction in Wwox-deficient cells after serial passage in culture. We determined that significantly reduced protein stability or loss-of-function A135P/V213G mutations in the DNA-binding domain of p53 caused defective induction of p21Cip1/Waf1 in late-passage Wwox-/- MEFs. Treatment of N-acetyl-L-cysteine prevented downregulation of cyclin-dependent kinase inhibitors and induced senescence in Wwox-/- MEFs. Our findings support an important role for fragile WWOX gene in inducing cellular senescence for maintaining genome integrity during DDR through alleviating oxidative stress.

Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 µM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

The Role of CD4/6 Inhibitors in Breast Cancer Treatment.

Over the last decade, treatment paradigms for breast cancer have undergone a renaissance, particularly in hormone-receptor-positive/HER2-negative breast cancer. These revolutionary therapies are based on the selective targeting of aberrancies within the cell cycle. This shift towards targeted therapies has also changed the landscape of disease monitoring. In this article, we will review the fundamentals of cell cycle progression in the context of the new cyclin-dependent kinase inhibitors. In addition to discussing the currently approved cyclin-dependent kinase inhibitors for breast cancer, we will explore the ongoing development and search for predictive biomarkers and modalities to monitor treatment.

Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and revisiting the clinical and preclinical pipeline.

Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin-dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino-pyrimidine is a well-represented scaffold. The three-nitrogen framework of amino-pyrimidine is a fundamental hinge-binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose-limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP-binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

Molecular dynamics simulation and in vitro evaluation of herb-drug interactions involving dietary polyphenols and CDK inhibitors in breast cancer chemotherapy.

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 µM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.

CDK7 inhibitors as anticancer drugs.

Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

Adjuvant cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive breast cancer: One Monarch to rule them all?

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has dramatically improved outcomes for patients with metastatic, hormone receptor (HR)-positive breast cancer. Because of the continued high rate of relapse in patients with node-positive, HR-positive disease, evaluating these agents in the adjuvant setting is the logical next step. Three adjuvant CDK inhibitor trials have been reported to date, with only 1 of them showing a statistical advantage for the CDK inhibitor in comparison with endocrine therapy alone. These trials have key similarities and differences that could explain the disparate results. The one positive trial has a relatively short follow-up, and continued analysis is critical to confirm the benefit of adjuvant CDK inhibition in this setting. It is imperative that predictive biomarkers be determined so that these agents can be used in the patients most likely to benefit and thus the additional toxicity and expense can be avoided in those who do not require these agents. LAY SUMMARY: There is a critical need for new agents to prevent relapse in patients with hormone receptor-positive breast cancer. Trials to date evaluating cyclin-dependent kinase inhibitors, which decrease how quickly cancer cells multiply, have shown mixed results, with only 1 trial demonstrating that these agents decrease recurrence.

Hyperactivation of cyclin A-CDK induces centrosome overduplication and chromosome tetraploidization in mouse cells.

Mammalian cyclin A-CDK (cyclin-dependent kinase) activity during mitotic exit is regulated by two redundant pathways, cyclin degradation and CDK inhibitors (CKIs). Ectopic expression of a destruction box-truncated (thereby stabilized) mutant of cyclin A in the mouse embryonic fibroblasts nullizygous for three CKIs (p21, p27, and p107) results in constitutive activation ("hyperactivation") of cyclin A-CDK and induces rapid tetraploidization, suggesting loss of the two redundant pathways causes genomic instability. To elucidate the mechanism underlying teraploidization by hyperactive cyclin A-CDK, we first examined if the induction of tetraploidization depends on specific cell cycle stage(s). Arresting the cell cycle at either S phase or M phase blocked the induction of tetraploidization, which was restored by subsequent release from the arrest. These results suggest that both S- and M-phase progressions are necessary for the tetraploidization by hyperactive cyclin A-CDK and that the tetraploidization is not caused by chromosome endoreduplication but by mitotic failure. We also observed that the induction of tetraploidization is associated with excessive duplication of centrosomes, which was suppressed by S-phase but not M-phase block, suggesting that hyperactive cyclin A-CDK promotes centrosome overduplication during S phase. Time-lapse microscopy revealed that hyperactive cyclin A-CDK can lead cells to bypass cell division and enter pseudo-G1 state. These observations implicate that hyperactive cyclin A-CDK causes centrosome overduplication, which leads to mitotic slippage and subsequent tetraploidization.

Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).

New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.

Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3ß inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies.

The serine/threonine protein kinases CDK2 and GSK-3ß are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3ß inhibitors targeting breast cancer (5a-g, 7a-h, and 13a-b). The N1 -unsubstituted oxindole derivatives, series 5, showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds 5d-f showed the most potent cytotoxic activity with IC50 of 3.41, 3.45 and 2.27 µM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 µM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC50 of 4.81 and 4.34 µM, respectively. On the other hand, the N1 -substituted oxindole derivatives, series 7 and 13, showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3ß enzyme inhibition assay of series 5 revealed that compounds 5d and 5f are showing potent dual CDK2/GSK-3ß inhibitory activity with IC50 of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3ß. The most potent compounds 5d-f caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3ß inhibition. Molecular docking studies showed that the newly synthesised N1 -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3ß. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3ß. Whereas, in series 7 and 13, the N1 -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.

Cyclin-dependent kinase activity is required for type I interferon production.

Recognition of nucleic acids results in the production of type I IFNs, which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes. In a search for modulators of this pathway, we discovered an unexpected requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and IFN-stimulated gene expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-ß mRNA induction, nor for the response to exogenous IFN-α/ß, but are critical for IFN-ß release into culture supernatants, suggesting a posttranscriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN-ß, in which IFN-ß mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-ß.

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

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.

Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells.

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.

Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment.

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.

Understanding the benefits and challenges of first-line cyclin-dependent kinases 4 and 6 inhibitors in advanced breast cancer among postmenopausal women.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.

The Role of CDKs and CDKIs in Murine Development.

Cyclin-dependent kinases (CDKs) and their inhibitors (CDKIs) play pivotal roles in the regulation of the cell cycle. As a result of these functions, it may be extrapolated that they are essential for appropriate embryonic development. The twenty known mouse CDKs and eight CDKIs have been studied to varying degrees in the developing mouse, but only a handful of CDKs and a single CDKI have been shown to be absolutely required for murine embryonic development. What has become apparent, as more studies have shone light on these family members, is that in addition to their primary functional role in regulating the cell cycle, many of these genes are also controlling specific cell fates by directing differentiation in various tissues. Here we review the extensive mouse models that have been generated to study the functions of CDKs and CDKIs, and discuss their varying roles in murine embryonic development, with a particular focus on the brain, pancreas and fertility.

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets.

Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019).

Sustained proliferative capacity and gene dysregulation are hallmarks of cancer. In mammalian cells, cyclin-dependent kinases (CDKs) control critical cell cycle checkpoints and key transcriptional events in response to extracellular and intracellular signals leading to proliferation. Significant clinical activity for the treatment of hormone receptor positive metastatic breast cancer has been demonstrated by palbociclib, ribociclib and abemaciclib, dual CDK4/6 inhibitors recently FDA-approved. SY-1365, a CDK7 inhibitor has shown initial encouraging data in phase I for solid tumors treatment. These results have rejuvenated the CDKs research field. This review provides an overview of relevant advances on CDK inhibitor research since 2015 to 2019, with special emphasis on transcriptional CDK inhibitors, new emerging strategies such as target protein degradation and compounds under clinical evaluation.