ArticleNature2014
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
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Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 535 papers, 2 of them syntheses that pooled it.
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535citing papers in PubMed, 2 pooled it
23.9field-weighted citation impact, top 1% of its field
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Who cites it
535 citing papers in PubMed, 2 syntheses or guidelines pooled it, 886 citations in OpenAlex.
- Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research.Nature communications · 2023Pooled it
- Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer.Frontiers in pharmacology · 2023Pooled it
- Discovery of azaindole/indole-fused pyrimidine tetracyclic scaffolds as novel potent CDK7 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization.Signal transduction and targeted therapy · 2026Article
- Sensitizing tumor response to topoisomerase I antibody-drug conjugate by selective CDK7 inhibition.Science advances · 2026Article
- CDK7, CDK9, or CDK11 inhibition reduces neutrophil-driven inflammation and tissue damage in experimental autoimmune models.Cell communication and signaling : CCS · 2026Article
- Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders.Journal of medicinal chemistry · 2026Article
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Pharmacological inhibition of CDK7 and CDK9 suppresses gastrointestinal (colon) cancer progression through modulation of stemness, epithelial-mesenchymal transition, and chemoresistance.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Discovery of ZJC-11 as a Novel Selective CDK7 Inhibitor for Treating Triple-Negative Breast Cancer by Inducing Cell Senescence.Journal of medicinal chemistry · 2026Article
- Pan-cancer multi-omics characterization of CDK12 and virtual screening of Vietnamese natural products for novel inhibitors.Molecular diversity · 2026Article
- Analysis of Confounding Factors in Reactive Cysteine Profiling Reveals Enhanced Chromatin-Protein Association via CDK7 Inhibition by THZ1.ACS chemical biology · 2026Article
- CDK9 and hematologic malignancies: pioneering novel therapeutic approaches.Clinical and experimental medicine · 2026Review
- Inhibition of RNA polymerase II-activating CDK9 and CDK12/13, but not of cell cycle relevant CDKs, induces apoptosis by downregulating the short-lived Bcl-2 proteins Mcl1 and Bfl1/A1.Cell death & disease · 2026Article
- ZNF274 constrains lineage plasticity and drives intrinsic resistance to CDK7 inhibitors in pancreatic cancer.Nature communications · 2026Article
- Genome-Wide CRISPR/Cas9 Screening Identifies Modulators of THZ1 Response in Acute Myeloid Leukemia.Biomedicines · 2026Article
- Super-enhancer-driven LncRNA MIR205HG promotes esophageal squamous cell carcinoma progression via glycolysis reprogramming.Journal of translational medicine · 2026Article
- CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma.EMBO molecular medicine · 2026Article
- Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders.bioRxiv : the preprint server for biology · 2026Article
475 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 8 institutions in 3 countries.
Nicholas Kwiatkowski1] 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].
Tinghu Zhang1] 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].
Peter B RahlWhitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Brian J AbrahamWhitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Jessica Reddy1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Scott B Ficarro1] 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.
Anahita DasturDepartment of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Arnaud Amzallag1] 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.
Sridhar Ramaswamy1] 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.
Bethany Tesar1] 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.
Catherine E JenkinsTerry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Nancy M HannettWhitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Douglas McMillin1] 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.
Takaomi Sanda1] 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.
Taebo SimChemical 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.
Nam Doo KimDaegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Korea.
Thomas Look1] 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.
Constantine S Mitsiades1] 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.
Andrew P WengTerry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Jennifer R Brown1] 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.
Cyril H BenesDepartment of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Jarrod A Marto1] 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.
Richard A Young1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nathanael S Gray1] 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.
Dana-Farber Cancer Institute · USHarvard University · USWhitehead Institute for Biomedical Research · USBC Cancer Agency · CADaegu-Gyeongbuk Medical Innovation Foundation · KRKorea Institute of Science and Technology · KRMassachusetts General Hospital · USMassachusetts Institute of Technology · US
Funding
VIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI MATTHEW G. VANDER HEIDEN · 1985 to 2026
$93.9MUCLA-Caltech Medical Scientist Training ProgramT32GM008042 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI AJIJOLA, OLUJIMI A, DAWSON, DAVID WAYNE · 1985 to 2023
$29.9MThe Molecular Function of D-cyclins in T-ALLP01CA109901 · NCI · DANA-FARBER CANCER INSTITUTE · PI YOUNG, RICHARD · 2004 to 2014
$19.6MTranscriptional Regulatory Networks in Living CellsR01HG002668 · NHGRI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI YOUNG, RICHARD · 2003 to 2016
$17.9MTranscriptional control of inhibitory synapse formationP01NS047572 · NINDS · DANA-FARBER CANCER INSTITUTE · PI STILES, CHARLES D · 2004 to 2013
$13.5MPharmaco Response Signatures and Disease MechanismU54HG006097 · NHGRI · HARVARD MEDICAL SCHOOL · PI MITCHISON, TIMOTHY J, SORGER, PETER KARL · 2010 to 2013
$9.7MDesign of inhibitors of drug-resistance protein kinasesR01CA130876 · NCI · DANA-FARBER CANCER INST · PI GRAY, NATHANAEL SCHIANDER · 2008 to 2012
$2.1MDevelopment and Application of Selective Covalent Cdk7 InhibitorsR01CA179483 · NCI · DANA-FARBER CANCER INST · PI GRAY, NATHANAEL SCHIANDER, MITSIADES, CONSTANTINE S. · 2014 to 2016
$1.5MDevelopment of deep proteomic sequencing platforms for molecular markers in DLBCLR21CA178860 · NCI · DANA-FARBER CANCER INST · PI DANIAL, NIKA N, MARTO, JARROD A. · 2013 to 2014
$412kNCI NIH HHS CA109901NCI NIH HHS CA178860-01NCI NIH HHS P30 CA014051NCI NIH HHS R01 CA130876NCI NIH HHS R01 CA130876-04NCI NIH HHS R01 CA179483NCI NIH HHS R21 CA178860NHGRI NIH HHS HG002668NHGRI NIH HHS R01 HG002668NHGRI NIH HHS U54 HG006097NHGRI NIH HHS U54 HG006097-02NIGMS NIH HHS T32 GM008042NINDS NIH HHS P01 NS047572NINDS NIH HHS P01 NS047572-10
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.
Indexed as
Antineoplastic AgentsCell Line, TumorCell ProliferationCell SurvivalCore Binding Factor Alpha 2 SubunitCyclin-Dependent KinasesCysteineEnzyme InhibitorsGene Expression Regulation, NeoplasticHumansJurkat CellsPhenylenediaminesPhosphorylationPrecursor T-Cell Lymphoblastic Leukemia-LymphomaPyrimidinesAntineoplastic AgentsCore Binding Factor Alpha 2 SubunitCyclin-Dependent KinasesCysteineEnzyme InhibitorsPhenylenediaminesPyrimidines
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