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| Status |
Public on Jan 04, 2019 |
| Title |
Development of a selective CDK7 covalent inhibitor reveals predominant cell cycle phenotype |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well-defined. Some level of their distinct genomic occupancy may suggest a mechanism with specific target gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth/proliferation genes and BETs disproportionately at enhancer- regulated tissue specific genes. Depletion of E2F selectively down-regulates its regulatory axis and is generally synergistic with BET inhibition. In vivo, combined inhibition of BETs and E2F strongly reduces tumor growth, implicating E2F as a myeloma dependency that is potently leveraged with BET inhibition.
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| Overall design |
Cyclin-dependent kinase 7 (CDK7) regulates both cell cycle and transcription, but its precise role remains elusive. We previously described THZ1, a CDK7 inhibitor, which dramatically inhibits super-enhancer associated gene expression. However, potent CDK12/13 off-target activity obscured CDK7s contribution to this phenotype. Here, we describe the discovery of a highly selective, covalent CDK7 inhibitor. YKL-5-124 causes arrest at the G1/S transition and inhibition of E2F-driven gene expression; these effects are rescued by a CDK7 mutant unable to covalently engage YKL-5-124, demonstrating on-target specificity. Unlike THZ1, treatment with YKL-5-124 resulted in no change to Pol II CTD phosphorylation; however, inhibition could be reconstituted by combining YKL-5-124 and THZ531, a selective CDK12/13 inhibitor, revealing potential redundancies in CDK control of gene transcription. These findings highlight the importance of CDK7/12/13 polypharmacology for anti-cancer activity of THZ1 and posit that selective inhibition of CDK7 may be useful for treatment of cancers marked by E2F misregulation.
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| Contributor(s) |
Olson CM, Liang Y, Park WD, Elsarrag SZ, Lin CY, Kwiatkowski N, Gray NS |
| Citation(s) |
30905681 |
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| Submission date |
Jan 03, 2019 |
| Last update date |
Jan 13, 2022 |
| Contact name |
Charles Yang Lin |
| E-mail(s) |
charles.y.lin@bcm.edu
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| Phone |
6172764723
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| Organization name |
Baylor College of Medicine
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| Department |
Molecular and Human Genetics
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| Street address |
1 Baylor Plaza
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| City |
Houston |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (42)
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| Relations |
| BioProject |
PRJNA512643 |
| SRA |
SRP175087 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE124607_genes.fpkm_table.txt.gz |
2.6 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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