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| Status |
Public on Mar 20, 2023 |
| Title |
VIP152 is a Selective CDK9 Inhibitor with Pre-Clinical In Vitro and In Vivo Efficacy in Chronic Lymphocytic Leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors (ibrutinib or acalabrutinib) and BCL2 antagonists (venetoclax). When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by releasing RNA Polymerase II (POLII) from proximal-promoter pause by way of phosphorylation. The transcripts regulated by P-TEFb are frequently dysregulated in solid tumors and hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. This is due to lack of selective inhibitors and undesirable side-effect profiles of less selective inhibitors. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death as measured by apoptosis in CLL cell lines and primary patient samples. Transcriptome analysis revealed compensatory upregulation in translation machinery and inhibition of RNA degradation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs CDK9 binding partners such as HEXIM1, MEPCE, and LARP7. Finally, C57BL/6J immune competent mice were engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with either VIP152 or vehicle. VIP152-treated mice had a reduction of blood disease over time and an improved overall survival. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
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| Overall design |
We analyzed total cellular RNA from 4 different treatment naïve CLL patients following treatment with either DMSO or 1µM VIP152
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| Contributor(s) |
Sher SA, Lapalombella R, Byrd JC, Yan P |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Mar 21, 2022 |
| Last update date |
Mar 20, 2023 |
| Contact name |
Steven Sher |
| E-mail(s) |
stevenslinux@gmail.com
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| Organization name |
The Ohio State University
|
| Department |
Division of Hematology, Department of Internal Medicine
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| Lab |
Experimental Hematology Laboratory
|
| Street address |
410 W. 12th Ave.
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43210 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA818165 |
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