ArticleProceedings of the National Academy of Sciences of the United States of America2006
Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 108 citations in OpenAlex.
- Intrinsic cellular resistance to BCR::ABL1 inhibitors.Haematologica · 2026Review
- 3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development.Pharmaceuticals (Basel, Switzerland) · 2024Review
- New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs.Pharmaceutics · 2024Article
- Recent Developments and Future Perspectives of Purine Derivatives as a Promising Scaffold in Drug Discovery.Current topics in medicinal chemistry · 2024Review
- Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.Blood advances · 2023Article
- Article
- Momelotinib is a highly potent inhibitor of FLT3-mutant AML.Blood advances · 2022Article
- Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.International journal of molecular sciences · 2020Review
- Natural-Based Indirubins Display Potent Cytotoxicity toward Wild-Type and T315I-Resistant Leukemia Cell Lines.Journal of natural products · 2016Article
- Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics.PLoS computational biology · 2015Article
- Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance.Scientific reports · 2015Article
- A method for screening and validation of resistant mutations against kinase inhibitors.Journal of visualized experiments : JoVE · 2014Article
- Energetic dissection of Gleevec's selectivity toward human tyrosine kinases.Nature structural & molecular biology · 2014Article
- Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance.Chemical biology & drug design · 2013Article
- Overcoming AC220 resistance of FLT3-ITD by SAR302503.Blood cancer journal · 2013Article
- Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival.Blood · 2012Article
- Abl kinase constructs expressed in bacteria: facilitation of structural and functional studies including segmental labeling by expressed protein ligation.Molecular bioSystems · 2012Article
- SRC points the way to biomarkers and chemotherapeutic targets.Genes & cancer · 2012Article
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 1 country.
Funding
Abstract
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM(R)) BCR/ABL kinase variants. Both compounds potently inhibit most IM(R) variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
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Registered trials
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.