ArticleProceedings of the National Academy of Sciences of the United States of America2005
A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 221 citations in OpenAlex.
- Molecular biology of the novel anticancer medications: a focus on kinases inhibitors, biologics and CAR T-cell therapy.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Pharmacological Phase I Clinical Trials in Pediatric Brain Tumors (1990-2024): A Historical Perspective.Oncology research · 2025Review
- The prospect of substrate-based kinase inhibitors to improve target selectivity and overcome drug resistance.Chemical science · 2024Review
- Screening and Activity Evaluation of Novel BCR-ABL/T315I Tyrosine Kinase Inhibitors.Current medicinal chemistry · 2024Article
- Review
- Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update.Frontiers in pharmacology · 2022Review
- The Discovery of Novel BCR-ABL Tyrosine Kinase Inhibitors Using a Pharmacophore Modeling and Virtual Screening Approach.Frontiers in cell and developmental biology · 2021Article
- Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis.International journal of molecular sciences · 2020Review
- Kinase-targeted cancer therapies: progress, challenges and future directions.Molecular cancer · 2018Review
- Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance.Scientific reports · 2015Article
- Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges.ACS chemical biology · 2015Review
- A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2014Article
- A novel quantitative kinase assay using bacterial surface display and flow cytometry.PloS one · 2013Article
- ON01210.Na (Ex-RAD®) mitigates radiation damage through activation of the AKT pathway.PloS one · 2013Article
- Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia.Journal of blood medicine · 2012Article
- Tyrosine kinase inhibitors: Multi-targeted or single-targeted?World journal of clinical oncology · 2011Article
- A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies: the road not taken.Current medicinal chemistry · 2011Review
- Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia.Revista brasileira de hematologia e hemoterapia · 2011Article
- A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.Journal of medicinal chemistry · 2010Article
- Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming.Oncogene · 2010Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. In our quest to develop new BCR-ABL inhibitors, we chose to target regions outside the ATP-binding site of this enzyme because these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Here we describe the activity of one compound, ON012380, that can specifically inhibit BCR-ABL and induce cell death of Ph+ CML cells at a concentration of <10 nM. Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.
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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.