Abstract
THZ1 is a selective CDK7 inhibitor that preferentially diminishes transcription in cancer cells.
Major finding: THZ1 is a selective CDK7 inhibitor that preferentially diminishes transcription in cancer cells.
Mechanism: THZ1 covalently binds Cys312 outside the kinase domain of CDK7 to inhibit RNAPII phosphorylation.
Impact: Selective targeting of aberrant transcriptional regulation may serve as a therapeutic strategy.
Oncogenic transcription factors utilize the general transcriptional machinery to drive tumorigenesis, but targeting transcription factors therapeutically has proven to be a difficult proposition. An important regulator of the transcriptional machinery is cyclin-dependent kinase 7 (CDK7), which modulates transcription by phosphorylating the C-terminal domain of RNA polymerase II (RNAPII). Utilizing cell-based screening and in vitro assays, Kwiatkowski, Zhang, and colleagues identified THZ1 as a covalent, irreversible CDK7 inhibitor that interacts with cysteine 312, which is unique to CDK7 and is located outside its kinase domain, thus making THZ1 selective for CDK7. More than half of cancer cell lines screened demonstrated sensitivity to THZ1, which elicited a decrease in proliferation and an increase in apoptosis, and gene ontology analyses showed enrichment of oncogenic transcription factors and regulators of RNAPII-driven transcription in these THZ1-sensitive cell lines. THZ1 was particularly effective in T-cell acute lymphoblastic leukemia (T-ALL) cell lines with dysregulated transcription factors, as well as in patient-derived T-ALL and chronic lymphocytic leukemia cells and T-ALL xenografts. Importantly, THZ1 treatment was well tolerated in tumor-bearing mice and induced cell-cycle arrest but not apoptosis in nontransformed cell lines, suggesting that normal cells are relatively insensitive to transcriptional disruption by CDK7 inhibition. In T-ALL cells, steady-state levels of mRNA decreased over time and RNAPII occupancy was diminished across the genome, both at gene promoters and in gene bodies, upon treatment with THZ1, consistent with the role of CDK7 in regulating transcriptional initiation and pausing. In response to low-dose treatment with THZ1, transcription of runt-related transcription factor 1 (RUNX1) was most profoundly downregulated, preventing activation of the RUNX1-driven transcriptional program, which is implicated in leukemia. In sum, these data uncover a novel covalent, selective CDK7 inhibitor that preferentially targets cancer-associated transcriptional machinery and transcription factor networks.
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