期刊
LEUKEMIA
卷 29, 期 3, 页码 586-597出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.245
关键词
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资金
- National Institutes of Health (NIH) [HL082978-01, CA046939-23, R01CA178397]
- LLS [SCOR7005-11, 5090-12, SLP-8002-14]
- NIH [R01CA178397, CA093247]
- American Society of Hematology
- petascale computing Research Award at the Extreme Science and Engineering Discovery Environment (XSEDE) supercomputers [TG-CHE120086]
- National Science Foundation [OCI-1053575]
- Department of Medicinal Chemistry
- Austrian Science Fund (FWF) [SFBF47]
- National Sciences and Engineering Research Council
- Canadian Breast Cancer Research Foundation
- Discovery Grant [257588]
- Ontario Ministry of Research and Innovation Early Researcher Award
- [P30 CA042014]
- [5P30CA042014-24]
- Alberta Innovates [201201230] Funding Source: researchfish
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [0910735] Funding Source: National Science Foundation
Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen-deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 mu M) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.
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