title: Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
abstract: 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.
authors.affiliation: 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].
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.affiliation: 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].
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Rahl
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Reddy
authors.affiliation: 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.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Anahita
authors.initials: A
authors.lastname: Dastur
authors.affiliation: 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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Amzallag
authors.affiliation: 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.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: 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.
authors.forename: Bethany
authors.initials: B
authors.lastname: Tesar
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Jenkins
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Hannett
authors.affiliation: 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.
authors.forename: Douglas
authors.initials: D
authors.lastname: McMillin
authors.affiliation: 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.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.affiliation: 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.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Daegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Look
authors.affiliation: 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.
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.affiliation: 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.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: 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.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: 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.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003545:Cysteine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D010655:Phenylenediamines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors; D010655:Phenylenediamines; D011743:Pyrimidines; D018844:Cyclin-Dependent Kinases; D003545:Cysteine