Dinaciclib

Treatment options for colorectal cancer (CRC), especially in advanced stages are still insufficient. There, the discovery of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was a bright spot. However, most cancers show resistance toward apoptotic signals. Cyclin-dependent kinase 9 (CDK9) plays a crucial role in cell cycle progression in most tissues. We recently demonstrated the role of CDK9 in mediating TRAIL resistance. In this work, we investigated the role of CDK9 in colorectal cancer...

The ability to address the cell cycle in cancer therapy brings up new medication development possibilities. Cyclin-dependent kinases are a group of proteins that control the progression of the cell cycle. The CDK/cyclin complexes are activated when specific CDK sites are phosphorylated. Because of their non-selectivity and severe toxicity, most first-generation CDK inhibitors (also known as pan-CDK inhibitors) have not been authorized for clinical usage. Despite this, significant progress has been made in allowing pan-CDK inhibitors to be employed in clinical settings...

Targeting cyclin-dependent kinases (CDKs) has recently emerged as a promising therapeutic approach against cancer. However, the anticancer mechanisms of different CDK inhibitors (CDKIs) are not well understood. Our recent study revealed that selective CDK4/6 inhibitors sensitize colorectal cancer (CRC) cells to therapy-induced apoptosis by inducing Death Receptor 5 (DR5) via the p53 family member p73. In this study, we investigated if this pathway is involved in anticancer effects of different CDKIs. We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation...

While specific cell signaling pathway inhibitors have yielded great success in oncology, directly triggering cancer cell death is one of the great drug discovery challenges facing biomedical research in the era of precision oncology. Attempts to eradicate cancer cells expressing unique target proteins, such as antibody-drug conjugates (ADCs), T-cell engaging therapies, and radiopharmaceuticals have been successful in the clinic, but they are limited by the number of targets given the inability to target intracellular proteins...

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes...

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease (MRD) have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-ALL but with limitations as monotherapy...

Targeting cancer cell exosome release and biogenesis represents a potentially efficient means to treat tumors and prevent cancer recurrence/metastasis; however, the complexity and time-consuming nature of currently employed methods to purify and characterize exosomes represent obstacles to progression. Herein, we describe a rapid, convergent, and cost-efficient strategy to analyze candidate U.S. Food and Drug Administration (FDA)-approved drugs that inhibit exosome release and/or biogenesis using breast cancer cell line models in the hope of repurposing them for the clinical treatment of metastatic tumors...

Dinaciclib is a selective cyclin-dependent kinase inhibitor, but its radiosensitizing effect remains unclear. The aim of this study is to investigate the radiosensitizing effect of Dinaciclib on cervical cancer cells. Two cervical cancer cell lines, Hela and Siha, were selected, and the IC50 was determined by CCK8. The radiosensitizing effect of Dinaciclib was verified by plate cloning assay, and the G2/M phase arrest and apoptosis of IR cells were verified by flow cytometry. Immunofluorescence assay was used to verify the formation of γH2AX foci following DNA damage...

BACKGROUND: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC...

A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc , VIf , VIg , VIi , and VIk have the highest antiproliferative activity. Compounds VIc , VIf , VIg , VIi , and VIk inhibited EGFR with IC50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAFV600E (IC50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI50 = 44 and 35 nM against four cancer cell lines, respectively)...

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Breast cancer (BC) is prevalent worldwide and is a leading cause of death among women. However, cell-surface glucose-regulated protein 78 (cs-GRP78) is overexpressed in several types of cancer and during pathogen infections. This study examines two well-known BC drugs approved by the FDA as BC treatments to GRP78. The first type consists of inhibitors of cyclin-based kinases 4/6, including abemaciclib, palbociclib, ribociclib, and dinaciclib. In addition, tunicamycin, and doxorubicin, which are among the most effective anticancer drugs for early and late-stage BC, are tested against GRP78...

Cervical cancer (CC) is the world's fourth most prevalent cancer among women. The mortality rate of cervical cancer increases each year due to a lack of early diagnosis. Our study aims to find potential genes linked to cervical cancer and validate the findings using docking analysis. The microarray datasets (GSE6791, GSE7803, GSE9750, GSE39001, GSE52903, GSE63514, and GSE75132) were downloaded from the GEO (Gene Expression Omnibus) database. A total of 1160 Differentially Expressed Genes (DEGs) were discovered using the R statistical language, including 825 up-regulated and 335 down-regulated genes...

Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g, 10a-i and 12a-d) as promising anticancer agents with CDK1 inhibitory activity...

Sepsis is a challenging clinical syndrome caused by a dysregulated host response to infection. Here, we identified an unexpected proseptic activity of aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages. Previous studies have suggested that ACOD1, also known as immune-responsive gene 1, is an immunometabolic regulator that favors itaconate production to inhibit bacterial lipopolysaccharide-induced innate immunity. We used next-generation sequencing of lipopolysaccharide-activated THP1 cells to demonstrate that ACOD1 accumulation confers a robust proinflammation response by activating a cytokine storm, predominantly through the tumor necrosis factor signaling pathway...

BACKGROUND: Hepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential...

Cyclin dependent kinases (CDKs) enzymes regulate cell proliferation and transcriptional processes and can be considered as important targets for the development of anticancer and antimicrobial drugs. In this work, novel benzothiazolyl pyrazolopyrimidine carboxamide and benzothiazolyl pyrazolopyrimidine carbonitrile derivatives were synthesized and characterized. The synthetic process was carried out via the reaction of ylidine benzothiazole derivatives with pyrazolocarboxamide and pyrazolocarbonitrile through a Michael addition pathway...

The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the killing of cancer cells with the potent cyclin-dependent kinase (CDK) inhibitor Dinaciclib (Dina). However, both optimal drug formulations and delivery strategies are yet to be established to facilitate the clinical application of the combination of EV-T and Dina...

Background: Immunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable. Methods: To find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes...

Cell cycle dysregulation is a characteristic hallmark of malignancies, which results in uncontrolled cell proliferation and eventual tumor formation. Cyclin-dependent kinase 1 (CDK1) is a member of the family of cell cycle regulatory proteins involved in cell cycle maintenance. Given that overexpression of CDK1 has been associated with cancer, CDK1 inhibitors may restore equilibrium to the skewed cell cycle system and operate as an effective therapeutic drug. This study aimed to identify and classify inhibitors having a higher affinity for CDK1 and also evaluate the expression pattern and prognostic relevance of CDK1 in a wide range of cancers...