16 results on '"Shinko Hayashi"'
Search Results
2. A Recurrent Point Clouds Selection Method for 3D Dense Captioning.
- Author
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Shinko Hayashi, Zhiqiang Zhang, and Jinja Zhou
- Published
- 2022
- Full Text
- View/download PDF
3. Data from Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity
- Author
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Reimar Abraham, Johannes Bange, Toshinori Agatsuma, Roger W. Chapman, Dieter Häussinger, Masaharu Hanai, Alberto Martinez, Emi Imai, Hiroyuki Hanzawa, Mizuki Takahashi, Shuntaro Saito, Mauricio Redondo-Müller, Jan-Peter A. Mayer, Peter Wirtz, Yoshinori Kashimoto, Hironobu Komori, Reimi Kawaida, Yoko Oda, Shinko Hayashi, Ichiro Watanabe, Katrin Gruner, Tanja Lange, Toshiaki Ohtsuka, Keisuke Fukuchi, and René Bartz
- Abstract
The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo. The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.
- Published
- 2023
4. A Recurrent Point Clouds Selection Method for 3D Dense Captioning
- Author
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Shinko Hayashi, Zhiqiang Zhang, and Jinja Zhou
- Published
- 2023
5. 808 Blocking 'don’t-eat-me' signal of CD47-SIRPα by anti-SIRPα antibody enhances anti-tumor efficacy of trastuzumab deruxtecan
- Author
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Mayumi Sue, Takuya Tsubaki, Yoko Ishimoto, Shinko Hayashi, Saori Ishida, Yoshitaka Isumi, Jun Ishiguro, Reimi Kawaida, Toshiaki Ohtsuka, Teiji Wada, Toshinori Agatsuma, and Norihito Kawasaki
- Published
- 2022
6. Novel anti-GARP antibody DS-1055a augments anti-tumor immunity by depleting highly suppressive GARP+ regulatory T cells
- Author
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Shoichi Maruyama, Shinko Hayashi, Teiji Wada, Daisuke Sugiyama, Michinori Kadokura, Atsushi Tanemura, Kazuki Hirahara, Masato Amano, Ichiro Watanabe, Shiho Kozuma, Megumi Miyamoto, Kenichi Wakita, Atsushi Okamoto, Masato Hata, Kazuki Satoh, Takahiko Sato, Saori Ishida, Hiroyoshi Nishikawa, Helmut Jonuleit, Toshinori Agatsuma, Yoichi Kobayashi, Andrea Tuettenberg, Kyungtaek Lim, and Kaori Fujimaki
- Subjects
0301 basic medicine ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,chemical and pharmacologic phenomena ,Mice, SCID ,Biology ,Monoclonal antibody ,T-Lymphocytes, Regulatory ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Mice, Inbred NOD ,Immunity ,Neoplasms ,Immune Tolerance ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Mice, Knockout ,Tumor microenvironment ,Antibodies, Monoclonal ,Membrane Proteins ,FOXP3 ,General Medicine ,Immunosurveillance ,030104 developmental biology ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,Cancer research ,biology.protein ,Female ,Immunotherapy ,Antibody - Abstract
Regulatory T (Treg) cells, which are essential for maintaining self-tolerance, inhibit anti-tumor immunity, consequently hindering protective cancer immunosurveillance, and hampering effective anti-tumor immune responses in tumor-bearing hosts. Here, we show that depletion of Treg cells via targeting glycoprotein A repetitions predominant (GARP) induces effective anti-tumor immune responses. GARP was specifically expressed by highly suppressive Treg cells in the tumor microenvironment (TME) of multiple cancer types in humans. In the periphery, GARP was selectively induced in Treg cells, but not in effector T cells, by polyclonal stimulation. DS-1055a, a novel afucosylated anti-human GARP monoclonal antibody, efficiently depleted GARP+ Treg cells, leading to the activation of effector T cells. Moreover, DS-1055a decreased FoxP3+CD4+ T cells in the TME and exhibited remarkable anti-tumor activity in humanized mice bearing HT-29 tumors. We propose that DS-1055a is a new Treg-cell-targeted cancer immunotherapy agent with augmentation of anti-tumor immunity.
- Published
- 2021
7. Abstract 1847: Anti-GARP antibody DS-1055a augments antitumor immunity by depleting highly suppressive GARP+ regulatory T cells
- Author
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Michinori Kadokura, Lim Kyungtaek, Shiho Kozuma, Andrea Tuettenberg, Ichiro Watanabe, Masato Amano, Atsushi Okamoto, Kazuki Satoh, Megumi Miyamoto, Teiji Wada, Shoichi Maruyama, Atsushi Tanemura, Takahiko Sato, Hiroyoshi Nishikawa, Daisuke Sugiyama, Kaori Fujimaki, Kazuki Hirahara, Kenichi Wakita, Helmut Jonuleit, Saori Ishida, Toshinori Agatsuma, Yoichi Kobayashi, Shinko Hayashi, and Masato Hata
- Subjects
Cancer Research ,Tumor microenvironment ,T cell ,FOXP3 ,Biology ,Immune checkpoint ,Immunosurveillance ,Immune system ,medicine.anatomical_structure ,Oncology ,Humanized mouse ,Cancer research ,medicine ,CD8 - Abstract
Immune checkpoint blockers (ICBs) have drastically changed the clinical care of cancer; however, the population of patients who can benefit is relatively small because of intrinsic or acquired resistance to immune therapy. To evade immune destruction, tumors exploit several distinct strategies including immunosuppressive cells such as regulatory T (Treg) cells. Treg cells, an essential component for maintaining self-tolerance, inhibit antitumor immunity, consequently hindering protective cancer immunosurveillance and hampering effective antitumor immune responses in tumor-bearing hosts. It is often reported that a high ratio of Treg cells to effector CD8+ T cells is associated with poor prognosis in patients with cancer, and Treg cells represent one of the most important factors associated with resistance to ICBs, suggesting that Treg cells represent a new promising target for anti-cancer therapy. In this study, we performed a comprehensive screening to identify a tumor-infiltrating Treg cell-specific molecule among immune cell subsets in humans. Glycoprotein A repetitions predominant (GARP) was identified as a suitable target for selective Treg cell depletion in the tumor microenvironment (TME) of multiple caner types. In the periphery, GARP was selectively induced in Treg cells, but not in effector T cells, by polyclonal stimulation in humans. DS-1055a, a novel afucosylated anti-human GARP antibody, effectively depleted GARP+ Treg cells, leading to the activation of effector T cells. Moreover, DS-1055a decreased FOXP3+CD4+ T cell counts in the TME and exhibited remarkable antitumor activity in a human peripheral blood mononuclear cell-transplanted humanized mouse model bearing HT-29 tumors. From these results, we propose that DS-1055a can be a new Treg cell-targeted regent that augments antitumor T cell immunity by depleting GARP+ Treg cells. Currently, a Phase I study of DS-1055a is on-going (NCT04419532). Citation Format: Kazuki Satoh, Yoichi Kobayashi, Kaori Fujimaki, Masato Hata, Shinko Hayashi, Saori Ishida, Daisuke Sugiyama, Takahiko Sato, Lim Kyungtaek, Megumi Miyamoto, Shiho Kozuma, Michinori Kadokura, Kenichi Wakita, Kazuki Hirahara, Masato Amano, Ichiro Watanabe, Atsushi Okamoto, Andrea Tuettenberg, Helmut Jonuleit, Atsushi Tanemura, Shoichi Maruyama, Toshinori Agatsuma, Teiji Wada, Hiroyoshi Nishikawa. Anti-GARP antibody DS-1055a augments antitumor immunity by depleting highly suppressive GARP+ regulatory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1847.
- Published
- 2021
8. DS-7080a, a Selective Anti-ROBO4 Antibody, Shows Anti-Angiogenic Efficacy with Distinctly Different Profiles from Anti-VEGF Agents
- Author
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Tatsuya Inoue, Yoshitaka Isumi, Toshinori Agatsuma, Yasushi Yoshigae, Shinko Hayashi, Toshiyuki Sato, and Jun Hasegawa
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,genetic structures ,Angiogenesis ,medicine.medical_treatment ,Basic fibroblast growth factor ,Biomedical Engineering ,choroidal neovascularization ,Article ,Neovascularization ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ranibizumab ,antibody ,ROBO4 ,medicine ,Animals ,Humans ,Fluorescein Angiography ,age-related macular degeneration ,vascular endothelial growth factor ,Vascular Endothelial Growth Factors ,business.industry ,Growth factor ,eye diseases ,Vascular endothelial growth factor ,Ophthalmology ,030104 developmental biology ,Choroidal neovascularization ,chemistry ,030221 ophthalmology & optometry ,Cancer research ,Human umbilical vein endothelial cell ,Hepatocyte growth factor ,sense organs ,medicine.symptom ,business ,medicine.drug - Abstract
Purpose Neovascular age-related macular degeneration (nAMD) results from choroidal neovascularization (CNV) and causes severe vision loss. Intravitreal anti-vascular endothelial growth factor (VEGF) therapies have significantly improved therapeutic outcomes; however, a substantial number of patients experience disease progression. Roundabout 4 (ROBO4) has been reported to be a vascular-specific protein that stabilizes vasculature in ocular pathological angiogenesis. To explore ROBO4 targeting as a novel treatment against neovascularization, we generated a humanized anti-human ROBO4 antibody, DS-7080a, and evaluated its efficacy. Methods ROBO4 mRNA in human whole eye cross-sections was examined by in situ hybridization. Human umbilical vein endothelial cell (HUVEC) migration was measured in the presence of VEGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or conditioned medium of primary human retinal pigment epithelial (HRPE) cells. CNV was induced in cynomolgus monkeys by laser irradiation. Vascular leakage was measured by fluorescein angiography, and pathological changes were determined by histology. Results ROBO4 mRNA was detected in choroidal vessels of nAMD patients. DS-7080a suppressed HGF- or bFGF-induced HUVEC migration in addition to that induced by VEGF. Further, HUVEC migration induced by HRPE-conditioned medium was inhibited by either DS-7080a or ranibizumab in a similar manner, and the combination of these showed further inhibition. In a laser-induced CNV monkey model, single intravitreous administration of 1.1 mg/eye of DS-7080a reduced the incidence of grade 4 leakage from 44.45% in control eyes to 1.85% (P < 0.05 by Dunnett's test). Conclusions Anti-ROBO4 antibody DS-7080a suppressed HUVEC migration in a distinctly different fashion from anti-VEGF agents and improved laser-induced CNV in non-human primates. Translational Relevance DS-7080a may be a novel treatment option for nAMD.
- Published
- 2020
9. Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity
- Author
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Yoko Oda, Hiroyuki Hanzawa, René Bartz, Mizuki Takahashi, Tanja Lange, Toshinori Agatsuma, Reimi Kawaida, Jan-Peter Andreas Mayer, Toshiaki Ohtsuka, Alberto J Martinez, Roger W. Chapman, Ichiro Watanabe, Johannes Bange, Yoshinori Kashimoto, Shinko Hayashi, Shuntaro Saito, Reimar Abraham, Masaharu Hanai, Emi Imai, Mauricio Redondo-Müller, Katrin Gruner, Hironobu Komori, Dieter Häussinger, Keisuke Fukuchi, and Peter Wirtz
- Subjects
0301 basic medicine ,Cancer Research ,Cell signaling ,medicine.drug_class ,Cholestyramine Resin ,Antineoplastic Agents ,Fibroblast growth factor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Bile acid sequestrant ,Ileum ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,Mice, Inbred BALB C ,Bile acid ,Chemistry ,Cancer ,Antibodies, Monoclonal ,FGF19 ,Sorafenib ,medicine.disease ,030104 developmental biology ,Oncology ,Gene Expression Regulation ,Liver ,030220 oncology & carcinogenesis ,Toxicity ,Cancer research ,NIH 3T3 Cells ,Female ,Liver cancer ,Signal Transduction - Abstract
The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects. U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo. The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.
- Published
- 2018
10. Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists
- Author
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Takanori Yamazaki, Kenji Wakabayashi, Kazuhiko Tamaki, Shoko Honzumi, Takahiro Yamaguchi, Daisuke Nakai, Naoki Terasaka, Yumi Matsui, Masayuki Yoshida, Masami Arai, Shinko Hayashi, and Hiroyuki Hanzawa
- Subjects
Models, Molecular ,Hydrocarbons, Fluorinated ,Stereochemistry ,Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Crystal structure ,Benzoates ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,Transcription (biology) ,Drug Discovery ,medicine ,Animals ,Humans ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,Orphan Nuclear Receptors ,medicine.anatomical_structure ,chemistry ,ABCA1 ,biology.protein ,Molecular Medicine - Abstract
To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.
- Published
- 2015
11. Synthesis and biological evaluation of novel (−)-cercosporamide derivatives as potent selective PPARγ modulators
- Author
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Kouichi Nakamura, Takeshi Honda, Jun Tanaka, Jun Ohsumi, Masanori Kuroha, Kenji Wakabayashi, Akihiro Furukawa, Satoko Wakimoto, Tsuyoshi Arita, Yumi Matsui, Shinko Hayashi, Osamu Suzuki, Makoto Mori, Takehiro Fukuzaki, Kazushi Araki, and Susumu Satoh
- Subjects
Models, Molecular ,medicine.medical_specialty ,Protein Conformation ,Potassium ,chemistry.chemical_element ,Chemistry Techniques, Synthetic ,Cercosporamide ,Genes, Reporter ,Oral administration ,Transcription (biology) ,Cell Line, Tumor ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Solubility ,Receptor ,Benzofurans ,Pharmacology ,Organic Chemistry ,General Medicine ,Peroxisome ,Rats ,Bioavailability ,PPAR gamma ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Female - Abstract
Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.
- Published
- 2012
12. Substituents at the naphthalene C3 position of (−)-Cercosporamide derivatives significantly affect the maximal efficacy as PPARγ partial agonists
- Author
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Takeshi Honda, Shinko Hayashi, Takehiro Fukuzaki, Kazushi Araki, Kenji Wakabayashi, Jun Ohsumi, Tsuyoshi Arita, Yumi Matsui, Susumu Satoh, Akihiro Furukawa, and Makoto Mori
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Naphthalenes ,Crystallography, X-Ray ,Biochemistry ,Partial agonist ,Cercosporamide ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Hypoglycemic Agents ,Receptor ,Molecular Biology ,Benzofurans ,Naphthalene ,Regulation of gene expression ,chemistry.chemical_classification ,Molecular Structure ,Organic Chemistry ,Peroxisome ,Ligand (biochemistry) ,PPAR gamma ,Gene Expression Regulation ,chemistry ,Molecular Medicine - Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential drug target for treating type 2 diabetes. The selective PPARγ modulators (SPPARMs), which partially activate the PPARγ transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARγ related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARγ transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARγ transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARγ partial agonist.
- Published
- 2012
13. Crystal Structure of the Extracellular Domain of Mouse RANK Ligand at 2.2-Å Resolution
- Author
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Shinko Hayashi, Tadashi Hata, Shuichiro Ito, Fumihiko Okada, Osamu Ubukata, and Kenji Wakabayashi
- Subjects
Models, Molecular ,musculoskeletal diseases ,Macromolecular Substances ,Stereochemistry ,Recombinant Fusion Proteins ,Protein subunit ,Molecular Sequence Data ,Osteoclasts ,Receptors, Cytoplasmic and Nuclear ,Crystallography, X-Ray ,Sensitivity and Specificity ,Biochemistry ,Receptors, Tumor Necrosis Factor ,Bone remodeling ,Mice ,Extracellular ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Lymphotoxin-alpha ,Molecular Biology ,Glycoproteins ,Membrane Glycoproteins ,Receptor Activator of Nuclear Factor-kappa B ,Sequence Homology, Amino Acid ,biology ,Activator (genetics) ,Chemistry ,RANK Ligand ,NF-kappa B ,Osteoprotegerin ,Cell Biology ,Ligand (biochemistry) ,Peptide Fragments ,Cell biology ,RANKL ,biology.protein ,Bone Remodeling ,Carrier Proteins ,Sequence Alignment - Abstract
Bone remodeling involves the resorption of bone by osteoclasts and the synthesis of bone matrix by osteoblasts. Receptor activator of NF-kappa B ligand (RANKL, also known as ODF and OPGL), a member of the tumor necrosis factor (TNF) family, triggers osteoclastogenesis by forming a complex with its receptor, RANK. We have determined the crystal structure of the extracellular domain of mouse RANKL at 2.2-A resolution. The structure reveals that the RANKL extracellular domain is trimeric, which was also shown by analytical ultracentrifugation, and each subunit has a beta-strand jellyroll topology like the other members of the TNF family. A comparison of RANKL with TNF beta and TNF-related apoptosis-inducing ligand (TRAIL), whose structures were determined to be in the complex form with their respective receptor, reveals conserved and specific features of RANKL in the TNF superfamily and suggests the presence of key residues of RANKL for receptor binding.
- Published
- 2002
14. Abstract 3852: U3-1784, a human anti-FGFR4 antibody for the treatment of cancer
- Author
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Keisuke Fukuchi, Tanja Lange, Mauricio Redondo-Müller, Ichiro Watanabe, Johannes Bange, Toshiaki Ohtsuka, René Bartz, Mizuki Takahashi, Shinko Hayashi, Reimar Abraham, Toshinori Agatsuma, and Katrin Gruner
- Subjects
0301 basic medicine ,Cancer Research ,biology ,Chemistry ,Cancer ,Fibroblast growth factor receptor 4 ,Gene mutation ,medicine.disease ,Ligand (biochemistry) ,Receptor tyrosine kinase ,Epitope ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Fibroblast growth factor receptor ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,biology.protein ,Receptor - Abstract
Fibroblast Growth Factor Receptor 4 (FGFR4) is the fourth member of the Fibroblast Growth Factor Receptor (FGFR) family of receptor tyrosine kinases. All of the FGFR's have been implicated in cancer development due to increased activation of their enzymatic activity either by gene mutation, over-expression or inadvertent ligand-mediated stimulation. One important alteration that may lead to FGFR4 activation in cancer is the overexpression of its ligand FGF19 in 20-40% of primary liver cancer. Here, we report the development of U3-1784, a phage display-derived fully human antibody that specifically binds to FGFR4 but not to isoforms of FGFR1-3. The antibody binds to an epitope in the putative ligand binding domain of the receptor and consequently inhibits ligand binding and downstream signaling. In a panel of 10 tumor models derived from hepatocellular carcinoma, U3-1784 significantly inhibits the growth of FGF19-expressing models up to 90% whereas models without FGF19 expression are insensitive. These results strongly suggest that the FGFR4/FGF19 axis is an oncogenic driver in hepatocellular carcinoma. U3-1784 is currently in phase I clinical trials. Citation Format: Rene Bartz, Keisuke Fukuchi, Tanja Lange, Katrin Gruner, Toshiaki Ohtsuka, Ichiro Watanabe, Shinko Hayashi, Mauricio Redondo-Müller, Mizuki Takahashi, Toshinori Agatsuma, Johannes Bange, Reimar Abraham. U3-1784, a human anti-FGFR4 antibody for the treatment of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3852.
- Published
- 2016
15. Pharmacology and in vitro profiling of a novel peroxisome proliferator-activated receptor γ ligand, Cerco-A
- Author
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Jun Ohsumi, Akihiro Furukawa, Jun Tanaka, Masanori Kuroha, Tsuneaki Ogata, Yumi Matsui, Satoko Wakimoto, Naomi Tanaka, Tomoko Inaba, Takuo Matsumoto, Ryo Okuyama, Kazushi Araki, Kenji Wakabayashi, Shoichi Kanda, and Shinko Hayashi
- Subjects
medicine.medical_specialty ,Pharmaceutical Science ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Fluorescence Polarization ,Pharmacology ,Biology ,Ligands ,Partial agonist ,chemistry.chemical_compound ,Internal medicine ,Adipocyte ,Cell Line, Tumor ,medicine ,Adipocytes ,Animals ,Humans ,Receptor ,Benzofurans ,DNA Primers ,chemistry.chemical_classification ,Triglyceride ,Base Sequence ,Molecular Structure ,Cell Differentiation ,General Medicine ,Rats ,Rats, Zucker ,PPAR gamma ,Endocrinology ,chemistry ,Rosiglitazone ,Pioglitazone ,medicine.drug - Abstract
Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.
- Published
- 2011
16. Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives
- Author
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Tsuyoshi Arita, Shinko Hayashi, Kazushi Araki, Susumu Satoh, Masanori Kuroha, Jun Ohsumi, Akihiro Furukawa, Kenji Wakabayashi, and Yumi Matsui
- Subjects
Male ,Models, Molecular ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Peroxisome proliferator-activated receptor ,Carboxamide ,Crystallography, X-Ray ,Biochemistry ,Partial agonist ,Cercosporamide ,Mice ,Drug Discovery ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Hypoglycemic Agents ,Molecular Biology ,Benzofurans ,Heart weight ,chemistry.chemical_classification ,Organic Chemistry ,Ligand binding domain ,PPAR gamma ,Glucose ,chemistry ,Hyperglycemia ,Molecular Medicine - Abstract
In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.
- Published
- 2009
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