ArticleCancer cell2014
Drugging MYCN through an allosteric transition in Aurora kinase A.
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Article in Cancer cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 164 papers.
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164citing papers in PubMed
10.9field-weighted citation impact, top 1% of its field
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Who cites it
164 citing papers in PubMed, 274 citations in OpenAlex.
- Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Trial
- Paediatric therapeutic development workshop on osteosarcoma.British journal of cancer · 2026Review
- Targeting MYCN Degradation by HLB-0532259 Induces Senescence in Retinoblastoma.Investigative ophthalmology & visual science · 2026Article
- AURORA A interacts with DICER and SETD2 to promote S-phase progression.EMBO reports · 2026Article
- Targeting the MYCN interaction network in neuroblastoma.Bioscience reports · 2026Review
- Covalent Peptide-Based N-Myc/Aurora-A Inhibitors Bearing Sulfonyl Fluoride Warheads.Journal of peptide science : an official publication of the European Peptide Society · 2026Article
- Effect ofJCO precision oncology · 2026Article
- The N-Myc MB0-MBI region interacts specifically and dynamically with the N-lobe of Aurora kinase A.Nature communications · 2026Article
- LINC01963 promotes pancreatic ductal adenocarcinoma proliferation via METTL3/IGF2BP2 axis-mediated m⁶A modification of c-Myc.Journal of experimental & clinical cancer research : CR · 2026Article
- MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.Frontiers in immunology · 2026Review
- Targeting high-risk MYC-overexpressed osteosarcoma with an Aurora kinase inhibitor:--results from a pilot umbrella trial.NPJ precision oncology · 2025Article
- Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma.Journal of medicinal chemistry · 2025Article
- The role of DNA methylation in directing treatment in medulloblastoma.Epigenomics · 2025Review
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Small-Molecule Drugs in Pediatric Neuro-Oncology.Current oncology (Toronto, Ont.) · 2025Review
- Razing the scaffolding: the elimination of non-catalytic functions of kinases through targeted protein degradation.RSC medicinal chemistry · 2025Review
- Disruption of the KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models.The Journal of clinical investigation · 2025Article
- In-silico drug repositioning studies of Candida albicans Nitrogen permease reactivator 1 (Npr1) kinase.Scientific reports · 2025Article
- Interplay Between the Epigenome, the Microenvironment, and the Immune System in Neuroblastoma.Cancers · 2025Review
- Temporal myc dynamics permit mitotic bypass, promoting polyploid phenotypes.Cancer letters · 2025Review
104 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 8 institutions in 2 countries.
William Clay GustafsonDepartment of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Justin Gabriel MeyerowitzDepartments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Erin A NekritzDepartment of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Justin ChenDepartments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
Cyril BenesMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02114, USA.
Elise CharronDepartment of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Erin F SimondsDepartments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Robert SeegerDivision of Hematology/Oncology, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #57, Los Angeles, CA 90027, USA.
Katherine K MatthayDepartment of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Nicholas T HertzDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Martin EilersTheodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Würzburg, Germany.
Kevan M ShokatDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
William A WeissDepartment of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: waweiss@gmail.com.
University of California, San Francisco · USNeurological Surgery · USChildren's Hospital of Los Angeles · USHarvard University · USHoward Hughes Medical Institute · USUCSF Benioff Children's Hospital · USUCSF Helen Diller Family Comprehensive Cancer Center · USUniversity of Würzburg · DE
Funding
Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jennifer Leigh Clarke · 1999 to 2026
$209.7MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6MVascular endothelial cell integrins in angiogenesisP01CA081403 · NCI · CHILDREN'S HOSPITAL OF LOS ANGELES · PI SEEGER, ROBERT CHARLES · 2000 to 2014
$28.5MMouse models to discover new drivers of medulloblastomaR01CA159859 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI Michael D. Taylor, WILLIAM A WEISS · 2011 to 2026
$10.4MPharmaco Response Signatures and Disease MechanismU54HG006097 · NHGRI · HARVARD MEDICAL SCHOOL · PI MITCHISON, TIMOTHY J, SORGER, PETER KARL · 2010 to 2013
$9.7MRESEARCH TRAINING IN CHEMISTRY AND CHEMICAL BIOLOGYT32GM064337 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CRAIK, CHARLES SCOTT · 2002 to 2021
$7.8MResearch Training in Childhood CancerT32CA128583 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Eric Alejandro Sweet-Cordero · 2007 to 2026
$6.0MMurine Neuroblastoma Models for Preclinical TherapeuticsR01CA102321 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WEISS, WILLIAM A · 2003 to 2016
$3.4MMedulloblastoma and MetastasesR01CA148699 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI TAYLOR, MICHAEL D., WEISS, WILLIAM A · 2010 to 2014
$2.4MGenetic network analysis of cancer targetsU01CA176287 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WEISS, WILLIAM A · 2013 to 2016
$1.2MBlockade of p53 and Aurora A in Therapy Resistant NeuroblastomaK08NS079485 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GUSTAFSON, WILLIAM CLAY · 2012 to 2014
$552kTargeting the translational apparatus in MYCN-driven pediatric solid tumorsF30CA174154 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MEYEROWITZ, JUSTIN · 2013 to 2015
$107kHoward Hughes Medical InstituteNCI NIH HHS F30 CA174154NCI NIH HHS F30CA174154NCI NIH HHS L40 CA153057NCI NIH HHS P01 CA081403NCI NIH HHS P01CA081403NCI NIH HHS P30 CA082103NCI NIH HHS P30CA82103NCI NIH HHS R01 CA102321NCI NIH HHS R01CA102321NCI NIH HHS R01 CA148699NCI NIH HHS R01CA148699NCI NIH HHS R01 CA159859NCI NIH HHS R01CA159859NCI NIH HHS T32 CA128583NCI NIH HHS U01 CA176287NHGRI NIH HHS 1U54HG006097-01NHGRI NIH HHS U54 HG006097NIGMS NIH HHS T32 GM007618NIGMS NIH HHS T32 GM064337NINDS NIH HHS K08 NS079485NINDS NIH HHS K08NS079485
Abstract
MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.
Indexed as
Allosteric RegulationAnimalsAntineoplastic AgentsArea Under CurveAurora Kinase ACatalytic DomainCell Line, TumorCell SurvivalCrystallography, X-RayHumansMiceMice, Inbred NODMice, NudeMice, SCIDModels, MolecularNeuroblastomaAntineoplastic AgentsAURKA protein, humanAurora Kinase ACD532 compoundMYCN protein, humanN-Myc Proto-Oncogene ProteinNuclear ProteinsOncogene ProteinsPhenylurea CompoundsPyrimidines
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