Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma
Open accessAbstract
BACKGROUND: STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5. METHODS AND FINDINGS: An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice. CONCLUSIONS: LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.
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Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.
“These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
From Osteosarcoma (2022) · cites this paper as [219]
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- Authors
- Yu, P. Y., Gardner, H. L., Roberts, R., Cam, H., Hariharan, S., Ren, L., LeBlanc, A. K., Xiao, H., Lin, J., Guttridge, D. C., Mo, X., Bennett, C. E., Coss, C. C., Ling, Y., Phelps, M. A., Houghton, P., & London, C. A.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- The Ohio State University (US)
- Nationwide Children's Hospital (US)
- The University of Texas at San Antonio Health Science Center (US)
- National Institutes of Health (US)
- Tufts University (US)
- Corresponding author
- London, Cheryl A.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2017-07-27
- Volume
- 12
- Issue
- 7
- Pages
- e0181885
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5531494
- OpenAlex
- W2741632062
- Cited by
- 17
- References
- 42
- Citations by year
- 2023: 1 · 2022: 4 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 1
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Cancer Institute (P01 CA165995, P30 CA016058)
- National Center for Advancing Translational Sciences (UL1 TR001070)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3 inhibitor, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, sarcoma, STAT3 phosphorylation, fragment-based drug discovery, oral bioavailability, lung metastasis, tumor xenografts, STAT3 knockdown, target specificity, anticancer efficacy
- MeSH terms
- Aminopyridines, Animals, Cell Survival, Dogs, Female, Humans, Lung Neoplasms, Phosphorylation, Rhabdomyosarcoma, Sarcoma, Ewing, Osteosarcoma, Sulfonamides, Cytokines, Treatment Outcome, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, Mice
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