A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases
Open accessAbstract
Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR-ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.
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OPB-31121 showed a good pharmacokinetic profile but limited antitumor activity in patients with HCC, and long-term dosing resulted in high incidence of peripheral neuropathy.
“This molecule developed by Otsuka Pharmaceutical (Tokyo, Japan) showed a good pharmacokinetic profile (Hayakawa et al., 2013; Kim et al., 2013b; Bendell et al., 2014; Brambilla et al., 2015), but demonstrated limited antitumor activity in patients with HCC (Bendell et al., 2014). Furthermore, long-term dosing resulted in a high incidence of peripheral neuropathy”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hayakawa et al., 2013
Hayakawa et al. is cited for the good pharmacokinetic profile; the HCC activity claim is cited to Bendell et al., and the neuropathy statement has no citation attached in the supplied sentence. The Results discuss oral dosing and common toxicities, while the Discussion says the HCC study was ongoing, but neither section reports pharmacokinetic measurements or assesses the drug's pharmacokinetic profile (searched: pharmacokinetics, exposure, bioavailability and half-life). (LLM, conf=0.75)
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Research works printed but not linked: 38
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“This molecule developed by Otsuka Pharmaceutical (Tokyo, Japan) showed a good pharmacokinetic profile (Hayakawa et al., 2013; Kim et al., 2013b; Bendell et al., 2014; Brambilla et al., 2015), but demonstrated limited antitumor activity in patients with HCC (Bendell et al., 2014).”
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- Authors
- Hayakawa, F., Sugimoto, K., Harada, Y., Hashimoto, N., Ohi, N., Kurahashi, S., & Naoe, T.
- Affiliations
- Nagoya University (JP)
- Otsuka (Japan) (JP)
- Corresponding author
- Hayakawa, F
- Venue
- Blood Cancer Journal
- Published
- 2013-11-29
- Volume
- 3
- Issue
- 11
- Pages
- e166-e166
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC3880446
- OpenAlex
- W2041341438
- Cited by
- 108
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 3 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 18 · 2014: 11
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- Blood Cancer Journal (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, Labour and Welfare
- Otsuka Pharmaceutical
- Chugai Pharmaceutical
- Japan Society for the Promotion of Science (23659487, 25118711, 23591381, 25293218)
- Institute of American Cultures, University of California, Los Angeles
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT inhibitors, STAT3 phosphorylation, STAT5 phosphorylation, leukemia, multiple myeloma, Burkitt lymphoma, BCR-ABL, FLT3-ITD, JAK2 V617F mutation, drug resistance, anticancer activity, hematologic malignancies
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