Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Abstract

Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state 1 , but direct pharmacological inhibition of transcription factors has thus far proven difficult 2 . However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates 3 , including cyclin-dependent kinases (CDKs) 4 . Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state.

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

“…1A). We next tested inhibitors of TFIIH CDK7 kinase activity (THZ) and the P-TEFb CDK9 inhibitor flavopiridol (FP) in our assay (47,48). Both THZ and flavopiridol have been shown previously to block transcription elongation in vitro (48,49).…”

“…The full-length labeled RNA run-off product of 548 nucleotides is indicated by the arrow. THZ is an inhibitor of the CDK7 kinase subunit of TFIIH, and FP is a P-TEFb inhibitor (47,48). PUGNAc and Thiamet G were added after a 30 h PIC formation step as our previous work suggested that OGA might be required for PIC formation (43).…”

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…Still, while CDK9 inhibition broadens the possibilities for ''anti-MYC'' therapy, its impact is not as great as MYC inhibition. Perhaps combinatorial therapies using the multikinase inhibitor sorafenib, a recently developed covalent CDK7 inhibitor that targets transcription regulation (Kwiatkowski et al 2014), or those targeting other MYC activities will synergize with CDK9 inhibition in producing strong anti-tumor effects.…”

Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

“…Indeed flavopiridol, a broad-acting kinase inhibitor that potently inhibits both CDK7 and CDK9 activity, has shown some promise in the treatment of several types of hematologic malignancies [15]. Recently, a drug prototype that is a remarkably selective inhibitor of CDK7 has been described [16]. This compound, THZ1, achieves relative selectivity for CDK7 through a covalent binding mechanism mediated by a reactive cysteine residue located outside the kinase pocket.…”