Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

DSpace/Manakin Repository

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Citable link to this page

 

 
Title: Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Author: Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B; Abraham, Brian J; Reddy, Jessica; Ficarro, Scott B; Dastur, Anahita; Amzallag, Arnaud; Ramaswamy, Sridhar; Tesar, Bethany; Jenkins, Christopher R; Hannett, Nancy M; McMillin, Douglas; Sanda, Takaomi; Sim, Taebo; Kim, Nam Doo; Look, Thomas; Mitsiades, Constantine; Weng, Andrew P; Brown, Jennifer R; Benes, Cyril H.; Marto, Jarrod A; Young, Richard A; Gray, Nathanael S.

Note: Order does not necessarily reflect citation order of authors.

Citation: Kwiatkowski, N., T. Zhang, P. B. Rahl, B. J. Abraham, J. Reddy, S. B. Ficarro, A. Dastur, et al. 2014. “Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.” Nature 511 (7511): 616-620. doi:10.1038/nature13393. http://dx.doi.org/10.1038/nature13393.
Full Text & Related Files:
Abstract: Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state1, but direct pharmacological inhibition of transcription factors has thus far proven difficult2. However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates3, 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.
Published Version: doi:10.1038/nature13393
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244910/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13890593
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters