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Updated: Feb 7, 2026
Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma
Shiori Kinoshita1, Takashi Ishida2,3, Asahi Ito1
1Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Japan.
Abstract:
BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY 1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro Seven NK-cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a survival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potential for treating NK-cell leukemia/lymphoma.
Insights
BAY 1143572, a selective inhibitor of cyclin-dependent kinase 9, shows promise for treating aggressive natural killer (NK) cell leukemias. This drug reduced tumor cell infiltration and improved survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Natural killer (NK) cell leukemias/lymphomas, including extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia, are associated with poor prognoses.
- Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcription elongation and a potential therapeutic target in hematologic malignancies.
Purpose of the Study:
- To evaluate the therapeutic potential of BAY 1143572, a selective CDK9 inhibitor, against aggressive NK cell leukemias/lymphomas.
- To investigate the mechanism of action of BAY 1143572 in preclinical models of NK cell malignancies.
Main Methods:
- BAY 1143572 was tested in vitro on NK cell leukemia/lymphoma lines and primary patient cells.
- A xenogeneic mouse model was established using primary aggressive NK-cell leukemia cells to test BAY 1143572 in vivo.
- Effects on RNA polymerase II C-terminal domain phosphorylation, c-Myc and Mcl-1 levels, cell growth, apoptosis, tumor infiltration, and survival were assessed.
Main Results:
- BAY 1143572 inhibited CDK9, leading to reduced phosphorylation of RNA polymerase II C-terminal domain.
- This inhibition decreased c-Myc and Mcl-1 levels, causing growth arrest and apoptosis in NK cell lines and primary cells.
- In vivo administration of BAY 1143572 reduced tumor cell infiltration and improved survival in a mouse model of aggressive NK-cell leukemia.
Conclusions:
- BAY 1143572 effectively inhibits CDK9 and demonstrates preclinical efficacy against aggressive NK cell leukemias/lymphomas.
- The drug's mechanism involves downregulation of key oncogenic and anti-apoptotic proteins, leading to tumor cell death and reduced dissemination.
- BAY 1143572 represents a potential targeted therapy for patients with poor-prognosis NK cell malignancies.
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