Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo
Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irr...
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Published in | Cancer letters Vol. 534; p. 215613 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier B.V
28.05.2022
Elsevier Limited |
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Abstract | Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC50 0.38–0.98 μM) over Stat1 or Stat5 (IC50 > 15.8 μM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo.
•Azetidine-based compounds, exemplified by H182 inhibit Stat3 activity with nanomolar-sub-micromolar potency•Azetidine-based compounds irreversibly bind to Stat3•Mass spectrometry detected the covalent binding to the key residues, Cys328, Cys426, Cys468, and Cys542•H182, H120 and other azetidine compounds inhibit constitutive and ligand-induced Stat3 signaling in triple-negative breast cancer cells•H120 or H182 as a single agent inhibited growth of triple-negative breast tumor xenografts•H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse triple-negative breast cancer growth and improved survival in syngeneic models |
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AbstractList | Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC
0.38-0.98 μM) over Stat1 or Stat5 (IC
> 15.8 μM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo. Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC50 0.38–0.98 μM) over Stat1 or Stat5 (IC50 > 15.8 μM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo. Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC50 0.38–0.98 μM) over Stat1 or Stat5 (IC50 > 15.8 μM) in vitro. Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 (8e) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo. •Azetidine-based compounds, exemplified by H182 inhibit Stat3 activity with nanomolar-sub-micromolar potency•Azetidine-based compounds irreversibly bind to Stat3•Mass spectrometry detected the covalent binding to the key residues, Cys328, Cys426, Cys468, and Cys542•H182, H120 and other azetidine compounds inhibit constitutive and ligand-induced Stat3 signaling in triple-negative breast cancer cells•H120 or H182 as a single agent inhibited growth of triple-negative breast tumor xenografts•H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse triple-negative breast cancer growth and improved survival in syngeneic models Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 ( 9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC 50 0.38–0.98 μM) over Stat1 or Stat5 (IC 50 > 15.8 μM) in vitro . Mass spectrometry detected the Stat3 cysteine peptides covalently bound to the azetidine compounds, and the key residues, Cys426 and Cys468, essential for the high potency inhibition, were confirmed by site-directed mutagenesis. In triple-negative breast cancer (TNBC) models, treatment with the azetidine compounds inhibited constitutive and ligand-induced Stat3 signaling, and induced loss of viable cells and tumor cell death, compared to no effect on the induction of Janus kinase (JAK)2, Src, epidermal growth factor receptor (EGFR), and other proteins, or weak effects on cells that do not harbor aberrantly-active Stat3. H120 ( 8e ) and H182 as a single agent inhibited growth of TNBC xenografts, and H278 (hydrochloric acid salt of H182) in combination with radiation completely blocked mouse TNBC growth and improved survival in syngeneic models. We identify potent azetidine-based, selective, irreversible Stat3 inhibitors that inhibit TNBC growth in vivo . |
ArticleNumber | 215613 |
Author | Pan, Songqin Yue, Peibin Verma, Nagendra Sheffler, Douglas J. Tius, Marcus A. Zhu, Yinsong Mikhael, Simoun Nakamura, Kayo Turkson, James Cosford, Nicholas D.P. Chen, Yue Lopez-Tapia, Francisco Chen, Jasmine Kershaw, Kathleen M. Limpert, Allison S. Fu, Wenzhen Brotherton-Pleiss, Christine Medina-Kauwe, Lali Celeridad, Maria Shiao, Stephen L. Chen, Weiliang Alonso-Valenteen, Felix |
AuthorAffiliation | d Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA e Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA c Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA g Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA h W. M. Keck Proteomics Laboratory, University of California, Riverside, CA, 92521, USA a Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA b Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA f Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA |
AuthorAffiliation_xml | – name: e Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – name: b Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – name: f Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – name: a Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – name: c Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA – name: d Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA – name: g Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA – name: h W. M. Keck Proteomics Laboratory, University of California, Riverside, CA, 92521, USA |
Author_xml | – sequence: 1 givenname: Peibin surname: Yue fullname: Yue, Peibin organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – sequence: 2 givenname: Yinsong surname: Zhu fullname: Zhu, Yinsong organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – sequence: 3 givenname: Christine surname: Brotherton-Pleiss fullname: Brotherton-Pleiss, Christine organization: Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA – sequence: 4 givenname: Wenzhen surname: Fu fullname: Fu, Wenzhen organization: Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA – sequence: 5 givenname: Nagendra surname: Verma fullname: Verma, Nagendra organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – sequence: 6 givenname: Jasmine surname: Chen fullname: Chen, Jasmine organization: Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA – sequence: 7 givenname: Kayo surname: Nakamura fullname: Nakamura, Kayo organization: Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA – sequence: 8 givenname: Weiliang surname: Chen fullname: Chen, Weiliang organization: Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, HI, 96825, USA – sequence: 9 givenname: Yue surname: Chen fullname: Chen, Yue organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – sequence: 10 givenname: Felix surname: Alonso-Valenteen fullname: Alonso-Valenteen, Felix organization: Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – sequence: 11 givenname: Simoun surname: Mikhael fullname: Mikhael, Simoun organization: Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – sequence: 12 givenname: Lali surname: Medina-Kauwe fullname: Medina-Kauwe, Lali organization: Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – sequence: 13 givenname: Kathleen M. surname: Kershaw fullname: Kershaw, Kathleen M. organization: Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – sequence: 14 givenname: Maria surname: Celeridad fullname: Celeridad, Maria organization: Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA – sequence: 15 givenname: Songqin surname: Pan fullname: Pan, Songqin organization: W. M. Keck Proteomics Laboratory, University of California, Riverside, CA, 92521, USA – sequence: 16 givenname: Allison S. surname: Limpert fullname: Limpert, Allison S. organization: Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA – sequence: 17 givenname: Douglas J. surname: Sheffler fullname: Sheffler, Douglas J. organization: Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA – sequence: 18 givenname: Nicholas D.P. surname: Cosford fullname: Cosford, Nicholas D.P. organization: Cell and Molecular Biology of Cancer Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, La Jolla, CA, 92037, USA – sequence: 19 givenname: Stephen L. surname: Shiao fullname: Shiao, Stephen L. organization: Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA – sequence: 20 givenname: Marcus A. surname: Tius fullname: Tius, Marcus A. organization: Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo St, Honolulu, HI, 96813, USA – sequence: 21 givenname: Francisco surname: Lopez-Tapia fullname: Lopez-Tapia, Francisco organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA – sequence: 22 givenname: James orcidid: 0000-0002-6964-1602 surname: Turkson fullname: Turkson, James email: james.tusrkson@cshs.org organization: Department of Medicine, Division of Medical Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angenes, CA, 90048, USA |
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Keywords | Signal transducer and activator of transcription Antitumor cell effects Small-molecule inhibitors Covalent modification Tumor growth inhibition |
Language | English |
License | This is an open access article under the CC BY license. Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
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Snippet | Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies... |
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SubjectTerms | Animals Antitumor activity Antitumor cell effects Apoptosis Azetidines - pharmacology Breast cancer Cancer therapies Cell death Cell Line, Tumor Covalent modification Epidermal growth factor Fibroblasts Gene expression Humans Hydrochloric acid Janus kinase Kinases Laboratory animals Mass spectroscopy Mice Peptides Phosphorylation Proteins Scientific imaging Signal transducer and activator of transcription Signal Transduction Site-directed mutagenesis Small-molecule inhibitors Stat1 protein Stat3 protein STAT3 Transcription Factor - metabolism Stat5 protein Therapeutic targets Transcription Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Tumor growth inhibition Xenografts |
Title | Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo |
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