| Reference | 1. Nature. 2014 Jul 31;511(7511):616-20. doi: 10.1038/nature13393. Epub 2014 Jun 22.
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Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
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Kwiatkowski N(1), Zhang T(2), Rahl PB(3), Abraham BJ(3), Reddy J(4), Ficarro
SB(5), Dastur A(6), Amzallag A(7), Ramaswamy S(7), Tesar B(8), Jenkins CE(9),
Hannett NM(3), McMillin D(8), Sanda T(10), Sim T(11), Kim ND(12), Look T(13),
Mitsiades CS(8), Weng AP(9), Brown JR(8), Benes CH(6), Marto JA(5), Young RA(4),
Gray NS(14).
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Author information: <br>
(1)1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3]
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
Massachusetts 02142, USA [4].
(2)1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3].
(3)Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
Massachusetts 02142, USA.
(4)1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge,
Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA.
(5)1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Blais
Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115,
USA.
(6)Department of Medicine Massachusetts General Hospital Cancer Center and
Harvard Medical School, Charlestown, Massachusetts 02129, USA.
(7)1] Department of Medicine Massachusetts General Hospital Cancer Center and
Harvard Medical School, Charlestown, Massachusetts 02129, USA [2] Broad Institute
of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
(8)1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts 02115, USA [2] Department of Medicine,
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
02115, USA.
(9)Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British
Columbia V5Z 1L3, Canada.
(10)1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts 02215, USA [2] Cancer Science Institute of
Singapore, National University of Singapore, 117599 Singapore.
(11)Chemical Kinomics Research Center, Korea Institute of Science and Technology,
39-1, Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Korea, and KU-KIST Graduate
School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul
136-713, Korea.
(12)Daegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero,
Suseong-gu, Daegu 706-010, Korea.
(13)1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard
Medical School, Boston, Massachusetts 02215, USA [2] Division of
Hematology/Oncology, Children’s Hospital, Boston, Massachusetts 02115 USA.
(14)1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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Comment in
Cancer Cell. 2014 Aug 11;26(2):158-9.
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Tumour oncogenes include transcription factors that co-opt the general
transcriptional machinery to sustain the oncogenic state, but direct
pharmacological inhibition of transcription factors has so far proven difficult.
However, the transcriptional machinery contains various enzymatic cofactors that
can be targeted for the development of new therapeutic candidates, including
cyclin-dependent kinases (CDKs). Here we present the discovery and
characterization of a 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 human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional
sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells 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 the
key role of RUNX1 in the core transcriptional regulatory circuitry of these
tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide
an approach to identify and treat tumour types that are dependent on
transcription for maintenance of the oncogenic state.
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