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Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition.

ABSTRACT: Undermining transcriptional addiction, the dependence of cancers on selected transcriptional programs, is critically important for addressing cancers with high unmet clinical need. Cyclin-dependent kinase 9 (CDK9) has long been considered an actionable therapeutic target for modulating transcription in many diseases. This appeal is due to its role in coordinating the biochemical events that regulate RNA polymerase II (RNA Pol II) pause-release state, one that offers a way for attenuating transcriptional dysregulation driven by amplified or overexpressed transcription factors implicated in cancer. However, targeting CDK9 in the clinic has historically proven elusive, a challenge that stems from the often highly intolerable cytotoxicity attributed to its essentiality across many cell lineages and the polypharmacology of the first generation of pan-CDK inhibitors to reach the clinic. A new wave of highly selective molecules progressing through the early stages of clinical evaluation offers renewed hope.

SUBMITTER: Toure MA

PROVIDER: S-EPMC10035036 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition.

Toure Mohammed A MA Koehler Angela N AN

Biochemistry 20230228 6

Undermining transcriptional addiction, the dependence of cancers on selected transcriptional programs, is critically important for addressing cancers with high unmet clinical need. Cyclin-dependent kinase 9 (CDK9) has long been considered an actionable therapeutic target for modulating transcription in many diseases. This appeal is due to its role in coordinating the biochemical events that regulate RNA polymerase II (RNA Pol II) pause-release state, one that offers a way for attenuating transcr ...[more]

PMID: 36854448

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Project description:Cyclin-dependent kinase 9 (CDK9) is critical for RNA Polymerase II (Pol II) transcription initiation, elongation, and termination in several key biological processes including development, differentiation, and cell fate responses. A broad range of diseases are characterized by CDK9 malfunction, illustrating its importance in maintaining transcriptional homeostasis in basal- and signal-regulated conditions. Here we provide a historical recount of CDK9 discovery and the current models suggesting CDK9 is a central hub necessary for proper execution of different steps in the transcription cycle. Finally, we discuss the current therapeutic strategies to treat CDK9 malfunction in several disease states. Abbreviations: CDK: Cyclin-dependent kinase; Pol II: RNA Polymerase II; PIC: Pre-initiation Complex; TFIIH: Transcription Factor-II H; snoRNA: small nucleolar RNA; CycT: CyclinT1/T2; P-TEFb: Positive Transcription Elongation Factor Complex; snRNP: small nuclear ribonucleo-protein; HEXIM: Hexamethylene Bis-acetamide-inducible Protein 1/2; LARP7: La-related Protein 7; MePCE: Methylphosphate Capping Enzyme; HIV: human immunodeficiency virus; TAT: trans-activator of transcription; TAR: Trans-activation response element; Hsp70: Heat Shock Protein 70; Hsp90/Cdc37: Hsp90- Hsp90 co-chaperone Cdc37; DSIF: DRB Sensitivity Inducing Factor; NELF: Negative Elongation Factor; CPSF: cleavage and polyadenylation-specific factor; CSTF: cleavage-stimulatory factor; eRNA: enhancer RNA; BRD4: Bromodomain-containing protein 4; JMJD6: Jumonji C-domain-containing protein 6; SEC: Super Elongation Complex; ELL: eleven-nineteen Lys-rich leukemia; ENL: eleven-nineteen leukemia; MLL: mixed lineage leukemia; BEC: BRD4-containing Elongation Complex; SEC-L2/L3: SEC-like complexes; KAP1: Kruppel-associated box-protein 1; KEC: KAP1-7SK Elongation Complex; DRB: Dichloro-1-ß-D-Ribofuranosylbenzimidazole; H2Bub1: H2B mono-ubiquitination; KM: KM05382; PP1: Protein Phosphatase 1; CDK9i: CDK9 inhibitor; SHAPE: Selective 2'-hydroxyl acylation analyzed by primer extension; TE: Typical enhancer; SE : Super enhancer.

Dataset Information

Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition.

Publications

Addressing Transcriptional Dysregulation in Cancer through CDK9 Inhibition.

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