scholarly journals Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia

Oncotarget ◽  
2014 ◽  
Vol 6 (5) ◽  
pp. 2667-2679 ◽  
Author(s):  
Yuh-Ying Yeh ◽  
Rong Chen ◽  
Joshua Hessler ◽  
Emilia Mahoney ◽  
Amy M. Lehman ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Cyclin Dependent Kinase ◽  
Cdk9 Kinase Activity

Abstract 1470: The Kinase Activity of Cyclin-Dependent Kinase-9 is Required for Phosphorylation of p300 and its Histone Acetyltransferase Activity during Cardiomyocyte Hypertrophy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yoichi Sunagawa ◽  
Tatsuya Morimoto ◽  
Tomohide Takaya ◽  
Teruhisa Kawamura ◽  
Hiromichi Wada ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Kinase Activity ◽  
Histone Acetyltransferase ◽  
Single Amino Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Cyclin Dependent Kinase ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Functional Relationships ◽  
Cdk9 Kinase Activity

Introduction: A zinc finger protein GATA4 is one of the factors involved in transcriptional regulation during myocardial cell hypertrophy and forms a complex with an intrinsic histone acetyltransferase (HAT), p300. HAT activity of p300 is required for acetylation and the transcriptional activity of GATA4 as well as for cardiomyocyte hypertrophy and the development of heart failure in vivo . By tandem affinity purification and mass spectrometric analyses, we identified cyclin-dependent kinase-9 (Cdk9), a component of positive transcription elongation factor b, as a novel GATA4-binding partner. Cdk9 also formed a complex with p300 as well as GATA4. However, the precise functional relationships among p300, GATA4, and Cdk9 remain unknown. Methods and Results: A series of GST pull-down assays revealed that the N-terminal of Cdk9 bound to the N-terminal zinc finger domain of GATA4 and C/H-3 domain of p300, respectively. By chromatin immunoprecipitation and DNA pull-down assay, we showed that GATA4 recruited Cdk9 onto GATA elements within the endothelin-1 promoter. Immuno-precipitation followed by Western blotting demonstrated that intact p300 induced not only the acetylation of GATA4, but also the interaction between GATA4 and Cdk9. Furthermore, p300 induced the hyperphosphorylation of RNA Pol II, suggesting that p300 is involved in the regulation of Cdk9 kinase activity. All of these effects were inhibited by the co-expression of a dominant-negative form (DN-) of p300. Conversely, Cdk9 induced not only the hyperphos-phorylation of RNA Pol II, but also the phosphorylation of p300. Notably, Cdk9 induced the acetylation and DNA binding of GATA4. However, DN-Cdk9, which loses its kinase activity by a single amino acid substitution, was unable to achieve these, suggesting the requirement of Cdk9 kinase activity for p300 HAT activity. Finally, a Cdk9 kinase inhibitor, DRB, inhibited phenylephrine-induced hypertrophic responses as well as the acetylation of GATA4 in cardiomyocytes. Conclusion: These findings demonstrate that Cdk9 is required for the phosphorylation of p300 and its HAT activity, and forms a functional complex with p300/GATA4 during cardiomyocyte hypertrophy.

The Cyclin-Dependent Kinase Inhibitors Olomoucine and Roscovitine Arrest Human Fibroblasts in G1 Phase by Specific Inhibition of CDK2 Kinase Activity

1998 ◽  
Vol 245 (1) ◽  
pp. 8-18 ◽  
Author(s):  
Francesca Alessi ◽  
Santina Quarta ◽  
Monica Savio ◽  
Federica Riva ◽  
Laura Rossi ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Human Fibroblasts ◽  
G1 Phase ◽  
Specific Inhibition ◽  
Cyclin Dependent Kinase

scholarly journals Computational evaluation of potent 2-(1H-imidazol-2-yl) pyridine derivatives as potential V600E-BRAF inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Docking Studies ◽  
Major Protein ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Protein Target ◽  
Computational Evaluation ◽  
Better Than

Abstract Background V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Results Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. Conclusion The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

scholarly journals The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2396
Author(s):  
Nina Schoenwaelder ◽  
Inken Salewski ◽  
Nadja Engel ◽  
Mareike Krause ◽  
Björn Schneider ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Head And Neck ◽  
Kinase Inhibitors ◽  
In Vivo Studies ◽  
Specific Response ◽  
Cyclin Dependent Kinase ◽  
Systematic Analysis ◽  
Mhc I ◽  
Oncological Treatment

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

scholarly journals High expression of hypoxia inducible factor 1α related with acquired resistant to EGFR tyrosine kinase inhibitors in NSCLC

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian Jin ◽  
Feihua Huang ◽  
Xianrong Xu ◽  
Haidong He ◽  
Yingqing Zhang
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Hypoxia Inducible Factor ◽  
High Expression ◽  
Normal Lung ◽  
Nsclc Tissue ◽  
T790m Mutation ◽  
Level Group ◽  
Egfr Tkis

AbstractThe acquired resistance of the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a main factor leading to poor prognosis of non-small cell lung cancer (NSCLC), so we researched whether the high expression of hypoxia-inducible factor-1α (HIF-1α) in EGFR-TKIs sensitive NSCLC tissue tends to induce the acquired resistance. We detected the HIF-1α in normal lung tissue, EGFR-TKIs sensitive NSCLC tissue, the first generation EGFR-TKIs acquired resistant NSCLC tissue and acquired EGFR T790M mutation NSCLC tissue with the method of immunohistochemistry. Then, we compared the expression of HIF-1α in these tissues, and evaluate the effect of HIF-1α expression to the occurrence of acquired resistance. The expression of HIF-1α was much higher in the EGFR-TKIs sensitive NSCLC tissue than that in normal lung tissue. HIF-1α level became higher after the occurrence acquired resistance. There was negative correlation between HIF-1α level before receiving treatment and the time of acquired resistance occurring as well as the acquired EGFR T790M mutation occurring. As the treatment going on, EGFR-TKIs sensitivity rate of low HIF-1α level group was much higher than that of high level group. The high expression of HIF-1α related with the acquired resistance of the first generation EGFR-TKIs, and HIF-1α can be a biomarker to predict the early occurrence of acquired resistance.

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