Transcriptomic data of inhibition of CDK12 in GBM12 cell line by SR-4835 treatment
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ABSTRACT:
PROVIDER: PRJNA1309139 | ENA |
REPOSITORIES: ENA
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Project description:This dataset contains transcriptomic profiles of the human glioblastoma cell line GBM12 following treatment with SR-4835, a selective CDK12 inhibitor. GBM12 cells were treated with SR-4835 or vehicle control for 24 hours, and total RNA was extracted for RNA sequencing. The study aims to elucidate transcriptional changes associated with CDK12 inhibition in glioblastoma and to identify downstream targets or pathways affected by SR-4835.
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Project description:Transcriptomic changes after CDK12/13 inhibition by SR-4835 in ovarian cancer cell lines
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Project description:The CDK12 inhibitor, SR-4835, promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation, paving the way for more precise and effective therapeutic strategies in cancer treatment.
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Project description:The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here,we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. However, short genes such as MYC and enhancer RNAs are highly transcribed in the absence of CDK12 activity. Indeed, in HER2+ breast cancer, a malignancy where CDK12 is invariably co-amplified with HER2 and its expression correlates with disease status, CDK12 inhibition markedly elevates MYC expression to induce lethality. The dual effects of CDK12 inhibition elucidated herein clarify its role in transcriptional control and have significant translational implications.
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Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.
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