ArticleCell2018
Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.
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Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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93citing papers in PubMed
6.3field-weighted citation impact, top 3% of its field
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93 citing papers in PubMed, 148 citations in OpenAlex.
- Targeting casein kinase 1α-mediated FADD phosphorylation restores sensitivity in select CDK4/6 inhibitor-resistant breast cancer models.The Journal of clinical investigation · 2026Article
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- The kinase CK1α coordinates the initiation and termination of the cGAS-STING pathway.Cell death and differentiation · 2026Article
- MET-associated immune prognostic signature predicts survival and guides personalized therapy in glioma.Acta neuropathologica communications · 2026Article
- Novel therapeutic targets at the crossroad between epigenetics and signal transduction pathways in B-cell lymphomas.Clinical and experimental medicine · 2026Review
- The Contribution of Native Protein Complexes to Targeted Protein Degradation.ACS chemical biology · 2026Article
- Structural dynamics between Argonaute-2 and CK1α promote target RNA release in microRNA-mediated silencing.bioRxiv : the preprint server for biology · 2026Article
- Molecular Mechanisms of Symptom Fluctuations in Malignant Tumor Patients: Stable by Day and Severe at Night.Journal of Cancer · 2026Review
- Machine Learning-Based Virtual Screening for the Identification of Novel CDK-9 Inhibitors.Biomolecules · 2025Article
- Discovery of a "First-in-Class" Selective Multikinase (CDK4/6/9-AURKA/B) Inhibitor, LCI133, for Neuroblastoma.Journal of medicinal chemistry · 2025Article
- Emerging strategies and novel therapeutic targets in acute myeloid leukemia: current advances and future directions.Biomarker research · 2025Review
- A Critical Look at the Crystal Structures of cAMP-Dependent Protein Kinases.Kinases and phosphatases · 2025Article
- Focal adhesion kinase/Src family kinase axis-mediated tyrosine phosphorylation of metabolic enzymes facilitates tumor metastasis.Signal transduction and targeted therapy · 2025Article
- Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML.Journal of hematology & oncology · 2025Article
- ProteinsPlus: a publicly available resource for protein structure mining.Nucleic acids research · 2025Article
- PARInternational journal of molecular sciences · 2025Article
- Article
- Super-enhancers in immune system regulation: mechanisms, pathological reprogramming, and therapeutic opportunities.Frontiers in immunology · 2025Review
- Super enhancers as key drivers of gene regulatory networks in normal and malignant hematopoiesis.Frontiers in cell and developmental biology · 2025Review
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
33 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 6 institutions in 3 countries.
Waleed MinzelThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Avanthika VenkatachalamThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Avner FinkThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Eric HungThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Guy BrachyaThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Ido BurstainThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Maya ShahamThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Amitai RivlinThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Itay OmerThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Adar ZingerThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Shlomo EliasThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Hematology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Eitan WinterBioinformatics Unit of the I-CORE Computation Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Paul E ErdmanBioTheryX Inc., San Diego, CA, USA.
Robert W SullivanBioTheryX Inc., San Diego, CA, USA.
Leah FungBioTheryX Inc., San Diego, CA, USA.
Frank MercurioBioTheryX Inc., San Diego, CA, USA.
Dansu LiWuXi AppTec, Shanghai, China.
Joseph VaccaWuXi AppTec, Shanghai, China.
Nathali KaushanskyDepartment of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Liran ShlushDepartment of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Moshe OrenDepartment of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Ross LevineCenter for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eli PikarskyThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Pathology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Irit Snir-AlkalayThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Yinon Ben-NeriahThe Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: yinonb@ekmd.huji.ac.il.
BioTheryX (United States) · USWeizmann Institute of Science · ILHadassah Medical Center · ILWuXi AppTec (China) · CNIsraeli Centers for Research Excellence · ILMemorial Sloan Kettering Cancer Center · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Elisa de Stanchina · 1985 to 2026
$347.4MSynergistic role of signaling and epigenetics in leukemic transformationR35CA197594 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Ross L Levine · 2017 to 2026
$11.4MRole of TET2 mutations in malignant transformation and acute myeloid leukemiaR01CA173636 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI AIFANTIS, IANNIS, LEVINE, ROSS L · 2013 to 2022
$6.3MECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTERU10CA180827 · NCI · MONTEFIORE MEDICAL CENTER (BRONX, NY) · PI LEVINE, ROSS L, MELNICK, ARI M. · 2014 to 2018
$3.0MDynamics of Tumor Stem Cells in Cancer Initiation, Therapy, and ResistanceR01CA138234 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI LEVINE, ROSS L, MICHOR, FRANZISKA · 2008 to 2012
$3.0MThe cohesin complex as a tumor suppressor in myeloid leukemiaR01CA216421 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS, LEVINE, ROSS L · 2017 to 2021
$2.5MMolecular Pathogenesis and Therapy of ET and PMFR01CA151949 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI LEVINE, ROSS L · 2010 to 2016
$2.3MSingle-cell cytokine analysis to detect and measure human myelofibrosisU01DK104331 · NIDDK · YALE UNIVERSITY · PI FAN, RONG, LEVINE, ROSS L · 2014 to 2018
$1.9MGenetic Dissection of Acute Myeloid Leukemia.R01CA169784 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI AIFANTIS, IANNIS, LEVINE, ROSS L · 2014 to 2018
$1.8MSingle cell cytokine analysis of circulating malignant hematopoietic cellsR33CA196411 · NCI · YALE UNIVERSITY · PI FAN, RONG, LEVINE, ROSS L · 2015 to 2017
$1.2MMolecular genetic analysis of tyrosine kinases in myeloproliferative disordersK08HL082677 · NHLBI · SLOAN-KETTERING INST CAN RESEARCH · PI LEVINE, ROSS L · 2006 to 2010
$670kHigh Throughput Screen for JAK2V617F Mutant Selective InhibitorsR03DA026206 · NIDA · SLOAN-KETTERING INST CAN RESEARCH · PI LEVINE, ROSS L · 2008 to 2008
$25kNCI NIH HHS P30 CA008748NCI NIH HHS R01 CA138234NCI NIH HHS R01 CA151949NCI NIH HHS R01 CA169784NCI NIH HHS R01 CA173636NCI NIH HHS R01 CA216421NCI NIH HHS R33 CA196411NCI NIH HHS R35 CA197594NCI NIH HHS U10 CA180827NHLBI NIH HHS K08 HL082677NHLBI NIH HHS L30 HL078257NIDA NIH HHS R03 DA026206NIDDK NIH HHS U01 DK104331
Abstract
CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2
Indexed as
AnimalsApoptosisCasein Kinase IalphaCell ProliferationCyclin-Dependent Kinase 9Cyclin-Dependent KinasesDisease Models, AnimalDNA-Binding ProteinsEnhancer Elements, GeneticHematopoiesisHumansLeukemia, Myeloid, AcuteMiceMice, Inbred C57BLOncogene Proteins, FusionProtein Serine-Threonine KinasesCasein Kinase IalphaCdk7 protein, mouseCdk9 protein, mouseCyclin-Dependent Kinase 9Cyclin-Dependent KinasesDNA-Binding ProteinsOncogene Proteins, FusionProtein Serine-Threonine KinasesProto-Oncogene ProteinsTrp53 protein, mouseTumor Suppressor Protein p53acute myeloid leukemiablocking transcription elongationCDK7 inhibitorCDK9/P-TEFb inhibitorCKIα inhibitorMCL1 eliminationMDM2 abolishmentMYC eliminationp53 activationsuper-enhancer shutdown
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.