ArticleScience (New York, N.Y.)2024
Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
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Article in Science (New York, N.Y.), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
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88citing papers in PubMed
59.6field-weighted citation impact, top 1% of its field
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Who cites it
88 citing papers in PubMed, 136 citations in OpenAlex.
- Docirbrutinib is a pan-mutant BTK inhibitor and inhibits B-cell receptor signaling in chronic lymphocytic leukemia cells in preclinical and early clinical investigations.Blood cancer journal · 2026Trial
- Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study.Blood advances · 2025Trial
- Targeted proteoform degradation for precision drug design, delivery, and therapy.Drug delivery · 2026Review
- From prediction to performance:International journal of pharmaceutics: X · 2026Article
- Advances in molecular pathobiology of PCNSL - towards clinical implementation of novel diagnostics and therapeutics.Biomarker research · 2026Review
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Sequencing asymmetry: the case for caution before first-line pirtobrutinib in chronic lymphocytic leukemia.Annals of hematology · 2026Article
- Article
- PLCG2 exon-skipped variants: insights into their potential role in chronic lymphocytic leukemia.Blood advances · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Review
- Three generations, one target: BTK inhibitors in lymphoma.Blood advances · 2026Article
- Targeted protein degradation: bridging chemical biology and clinical translation.Acta pharmacologica Sinica · 2026Review
- Low-dose EGFR inhibition unlocks ferroptosis susceptibility to sensitize chemotherapy in EGFR-high triple-negative breast cancer.The Journal of biological chemistry · 2026Article
- Research Trends and Emerging Frontiers in Proteolysis Targeting Chimeras (PROTACs): A Bibliometric Analysis of 2630 Publications (2001-2025).Pharmaceuticals (Basel, Switzerland) · 2026Article
- Article
- Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader.ACS chemical biology · 2026Article
- More than an attachment module: covalent inhibitor warheads influence BTK dynamics and function.bioRxiv : the preprint server for biology · 2026Article
- Cyclin-Dependent Kinase 5 Contributes to Bruton's Tyrosine Kinase Inhibitor Resistance via the IRE1α/XBP1 Axis in Mantle Cell Lymphoma.Research square · 2026Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
53 authors at 9 institutions in 3 countries.
Skye Montoya *Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-2094-6923
Jessie Bourcier *Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0009-0008-2499-6064
Mark Noviski *Nurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0001-8072-1059
Hao Lu *Nurix Therapeutics, San Francisco, CA, USA.
Meghan C ThompsonLeukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0003-1462-4802
Alexandra ChirinoSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-5840-4986
Jacob JahnSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0003-0745-7049
Anya K SondhiSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-6570-7694
Stefan GajewskiNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0001-5432-0403
Ying Siow May TanNurix Therapeutics, San Francisco, CA, USA.ORCID 0009-0001-5417-8088
Stephanie YungNurix Therapeutics, San Francisco, CA, USA.
Aleksandra UrbanDepartment of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.ORCID 0000-0002-7299-4935
Eric WangThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Cuijuan HanThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.ORCID 0000-0002-7165-7785
Xiaoli MiMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0002-0348-1001
Won Jun KimMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0002-1816-6119
Quinlan SieversMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0003-4875-0022
Paul AugerNurix Therapeutics, San Francisco, CA, USA.ORCID 0009-0004-3686-465X
Hugo BousquetNurix Therapeutics, San Francisco, CA, USA.
Nivetha BrathabanNurix Therapeutics, San Francisco, CA, USA.
Brandon BravoNurix Therapeutics, San Francisco, CA, USA.
Melissa GessnerNurix Therapeutics, San Francisco, CA, USA.
Cristiana GuiducciNurix Therapeutics, San Francisco, CA, USA.
James N IulianoNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0003-1213-3292
Tim KaneNurix Therapeutics, San Francisco, CA, USA.ORCID 0009-0005-2073-8744
Ratul MukerjiNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0002-6835-3182
Panga Jaipal ReddyNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0002-4481-3631
Janine PowersNurix Therapeutics, San Francisco, CA, USA.
Mateo Sanchez Garcia de Los RiosNurix Therapeutics, San Francisco, CA, USA.
Jordan YeNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0002-4978-872X
Carla Barrientos RissoSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-6173-269X
Daniel TsaiSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-5123-3627
Gabriel PardoSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Ryan Q NottiLaboratory of Molecular Electron Microscopy, Rockefeller University, New York, NY, USA.ORCID 0000-0002-9197-6134
Alejandro PardoSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Maurizio AfferSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-7247-6273
Vindhya NawaratneSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Tulasigeri M TotigerSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0002-4262-4458
Camila Pena-VelasquezMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Joanna M RhodesDivision of Hematology-Oncology, Department of Medicine at Zucker School of Medicine at Hofstra/Northwell, CLL Research and Treatment Center, Lake Success, NY, USA.ORCID 0000-0002-5068-9040
Andrew D ZelenetzLymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0003-1403-6883
Alvaro AlencarSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Lindsey E RoekerMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0002-3806-059X
Sanjoy MehtaGene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.ORCID 0009-0006-8991-8425
Ralph GarippaGene Editing and Screening Core Facility, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Institute and Cancer Center, New York, NY, USA.
Adam LinleyDepartment of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.ORCID 0000-0002-8176-5560
Rajesh Kumar SoniProteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.ORCID 0000-0002-4556-4358
Sigrid S SkånlandMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0003-1630-356X
Robert J BrownNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0003-4929-4719
Anthony R MatoMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gwenn M HansenNurix Therapeutics, San Francisco, CA, USA.ORCID 0000-0003-2504-5849
Omar Abdel-WahabMolecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID 0000-0002-3907-6171
Justin TaylorSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.ORCID 0000-0003-4407-6325
Nurix (United States) · USUniversity of Miami · USMemorial Sloan Kettering Cancer Center · USJackson Laboratory · USOslo University Hospital · NOColumbia University · USHofstra University · USRockefeller University · USUniversity of Liverpool · GB
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI SELWYN M VICKERS · 1985 to 2026
$347.4MTumor Biology Research ProgramP30CA240139 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Stephen D. Nimer · 2019 to 2026
$24.1MThe Memorial Sloan Kettering Cancer Center SPORE in LeukemiaP50CA254838 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Eytan Stein · 2021 to 2026
$16.8MInstitutional Career Development CoreKL2TR001865 · NCATS · ROCKEFELLER UNIVERSITY · PI SCHLESINGER, SARAH JANE · 2016 to 2025
$8.7MGenetic and molecular basis for SRSF2 mutations in myelodysplasiaR01HL128239 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Omar Abdel-Wahab, Robert K Bradley · 2015 to 2026
$8.0MInterrogating the minor spliceosome to understand and treat leukemiaR01CA251138 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI ABDEL-WAHAB, OMAR, BRADLEY, ROBERT K · 2020 to 2024
$3.3MTargeting an RNA Binding Protein Network in Acute Myeloid LeukemiaR01CA242020 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI ABDEL-WAHAB, OMAR, AIFANTIS, IANNIS · 2020 to 2024
$2.7MUnderstanding and Targeting Aberrant RNA Splicing in LeukemiaR35CA304457 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Omar Abdel-Wahab · 2025 to 2026
$2.0MDefining the Biological and Mechanistic Implications of XPO1 Mutations in Hematologic MalignanciesK08CA230319 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI TAYLOR, JUSTIN · 2018 to 2023
$1.2MA Fast Pixel-Array Pilatus 2M Detector for Automated Macromolecular Crystallography Data CollectionS10OD026941 · OD · UNIVERSITY OF CALIFORNIA BERKELEY · PI ADAMS, PAUL DAVID · 2019 to 2019
$563kInvestigating Resistance Mechanisms to Non-covalent Bruton's Tyrosine Kinase Inhibitors and Therapeutic Approaches to Overcome Resistance for Patients with B-Cell MalignanciesF31CA275378 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MONTOYA, OLIVIA SKYE · 2022 to 2023
$94kNCATS NIH HHS KL2 TR001865NCI NIH HHS F31 CA275378NCI NIH HHS K08 CA230319NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA240139NCI NIH HHS P50 CA254838NCI NIH HHS R01 CA242020NCI NIH HHS R01 CA251138NCI NIH HHS R35 CA304457NHLBI NIH HHS R01 HL128239NIH HHS S10 OD026941
Abstract
Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
Indexed as
Agammaglobulinaemia Tyrosine KinaseDrug Resistance, NeoplasmIkaros Transcription FactorLeukemia, Lymphocytic, Chronic, B-CellProtein Kinase InhibitorsProteolysisHumansMutationPhosphorylationSignal TransductionAgammaglobulinaemia Tyrosine KinaseIkaros Transcription FactorIKZF1 protein, humanIKZF3 protein, humanProtein Kinase Inhibitors
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