Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma
Abstract: Multiple myeloma (MM) is a cancer of plasma cells that remains incurable despite advances in treatment options. In this study, a library of 216 clinically feasible small-molecule inhibitors was screened to identify agents that selectively inhibit MM cell proliferation. Enitociclib, a cycli...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328024000505 |
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| author | Son Tran Patrick Sipila Melanie M. Frigault Beatrix Stelte-Ludwig Amy J. Johnson Joseph Birkett Raquel Izumi Ahmed Hamdy Ranjan Maity Nizar J. Bahlis Paola Neri Aru Narendran |
| author_facet | Son Tran Patrick Sipila Melanie M. Frigault Beatrix Stelte-Ludwig Amy J. Johnson Joseph Birkett Raquel Izumi Ahmed Hamdy Ranjan Maity Nizar J. Bahlis Paola Neri Aru Narendran |
| author_sort | Son Tran |
| collection | DOAJ |
| description | Abstract: Multiple myeloma (MM) is a cancer of plasma cells that remains incurable despite advances in treatment options. In this study, a library of 216 clinically feasible small-molecule inhibitors was screened to identify agents that selectively inhibit MM cell proliferation. Enitociclib, a cyclin-dependent kinase 9–specific small-molecule inhibitor, was found to be highly effective in decreasing cell viability and inducing apoptosis in 4 MM cell lines. Enitociclib inhibited the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II at Ser2/Ser5 and repressed the protein expression of oncogenes c-Myc, myeloid cell leukemia-1 (Mcl-1), and proliferating cell nuclear antigen (PCNA) in MM cells. Additionally, enitociclib demonstrated synergistic effects with several anti-MM agents, including bortezomib, lenalidomide, pomalidomide, and venetoclax. These results suggest that enitociclib may represent a promising therapeutic option for the treatment of MM, either as a single agent or in combination with other anti-MM agents. |
| format | Article |
| id | doaj-art-9dd9856bbb354655ba59857c10757dcb |
| institution | Kabale University |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-9dd9856bbb354655ba59857c10757dcb2025-02-06T05:13:11ZengElsevierBlood Neoplasia2950-32802025-02-0121100050Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myelomaSon Tran0Patrick Sipila1Melanie M. Frigault2Beatrix Stelte-Ludwig3Amy J. Johnson4Joseph Birkett5Raquel Izumi6Ahmed Hamdy7Ranjan Maity8Nizar J. Bahlis9Paola Neri10Aru Narendran11Department of Oncology, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, University of Calgary, Calgary, AB, CanadaVincerx Pharma, Inc, Palo Alto, CAVincerx Pharma GmbH, Monheim, GermanyVincerx Pharma, Inc, Palo Alto, CAVincerx Pharma GmbH, Monheim, GermanyVincerx Pharma, Inc, Palo Alto, CAVincerx Pharma, Inc, Palo Alto, CADepartments of Hematology and Oncology, University of Calgary, Calgary, AB, CanadaDepartments of Hematology and Oncology, University of Calgary, Calgary, AB, CanadaDepartments of Hematology and Oncology, University of Calgary, Calgary, AB, CanadaDepartment of Oncology, University of Calgary, Calgary, AB, Canada; Correspondence: Aru Narendran, University of Calgary, 3330 Hospital Dr NW, HMRB 326, Calgary, AB, Canada, T2N 4N1;Abstract: Multiple myeloma (MM) is a cancer of plasma cells that remains incurable despite advances in treatment options. In this study, a library of 216 clinically feasible small-molecule inhibitors was screened to identify agents that selectively inhibit MM cell proliferation. Enitociclib, a cyclin-dependent kinase 9–specific small-molecule inhibitor, was found to be highly effective in decreasing cell viability and inducing apoptosis in 4 MM cell lines. Enitociclib inhibited the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II at Ser2/Ser5 and repressed the protein expression of oncogenes c-Myc, myeloid cell leukemia-1 (Mcl-1), and proliferating cell nuclear antigen (PCNA) in MM cells. Additionally, enitociclib demonstrated synergistic effects with several anti-MM agents, including bortezomib, lenalidomide, pomalidomide, and venetoclax. These results suggest that enitociclib may represent a promising therapeutic option for the treatment of MM, either as a single agent or in combination with other anti-MM agents.http://www.sciencedirect.com/science/article/pii/S2950328024000505 |
| spellingShingle | Son Tran Patrick Sipila Melanie M. Frigault Beatrix Stelte-Ludwig Amy J. Johnson Joseph Birkett Raquel Izumi Ahmed Hamdy Ranjan Maity Nizar J. Bahlis Paola Neri Aru Narendran Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma Blood Neoplasia |
| title | Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma |
| title_full | Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma |
| title_fullStr | Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma |
| title_full_unstemmed | Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma |
| title_short | Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma |
| title_sort | enitociclib a selective cdk9 inhibitor in vitro and in vivo preclinical studies in multiple myeloma |
| url | http://www.sciencedirect.com/science/article/pii/S2950328024000505 |
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