TAS-115 - CAS 1190836-34-0
Catalog number: B0084-475134
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C27H23FN4O4S
Molecular Weight:
518.56
COA:
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Targets:
c-Met/HGFR | VEGFR
Description:
This active molecular is a c-MET and VEGFR inhibitor which is selective and specific in vitro. In vivo studies, TAS-115 suppressed the progression of MET-inactivated tumor completely through blocking angiogenesis without toxicity and it also induced marked tumor shrinkage and prolonged survival in animal model. In Dec 2013, Phase-I development was ongoing in Japan. In Dec 2014, Taiho Pharmaceutical completed a phase I trial for Solid tumours in Japan. In Apr 2016, preclinical data was presented.
Purity:
98%
Appearance:
Powder
Synonyms:
4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide
Solubility:
Soluble in DMSO
Storage:
-20°C Freezer
MSDS:
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Application:
Solid tumours
Quality Standard:
In-house standard
Shelf Life:
2 month in rt, long time
Quantity:
Milligrams-Grams
Canonical SMILES:
O=C(NC(NC1=CC(F)=C(OC2=C(C=C(C(NC)=O)C(OC)=C3)C3=NC=C2)C=C1)=S)CC4=CC=CC=C4
Current Developer:
Originator:Taiho Pharmaceutical
1.Triple inhibition of EGFR, Met, and VEGF suppresses regrowth of HGF-triggered, erlotinib-resistant lung cancer harboring an EGFR mutation.
Nakade J;Takeuchi S;Nakagawa T;Ishikawa D;Sano T;Nanjo S;Yamada T;Ebi H;Zhao L;Yasumoto K;Matsumoto K;Yonekura K;Yano S J Thorac Oncol. 2014 Jun;9(6):775-83. doi: 10.1097/JTO.0000000000000170.
INTRODUCTION: ;Met activation by gene amplification and its ligand, hepatocyte growth factor (HGF), imparts resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer. We recently reported that Met activation by HGF stimulates the production of vascular endothelial growth factor (VEGF) and facilitates angiogenesis, which indicates that HGF induces EGFR-TKI resistance and angiogenesis. This study aimed to determine the effect of triple inhibition of EGFR, Met, and angiogenesis on HGF-triggered EGFR-TKI resistance in EGFR-mutant lung cancer.;METHODS: ;Three clinically approved drugs, erlotinib (an EGFR inhibitor), crizotinib (an inhibitor of anaplastic lymphoma kinase and Met), and bevacizumab (anti-VEGF antibody), and TAS-115, a novel dual TKI for Met and VEGF receptor 2, were used in this study. EGFR-mutant lung cancer cell lines PC-9, HCC827, and HGF-gene-transfected PC-9 (PC-9/HGF) cells were examined.;RESULTS: ;Crizotinib and TAS-115 inhibited Met phosphorylation and reversed erlotinib resistance and VEGF production triggered by HGF in PC-9 and HCC827 cells in vitro. Bevacizumab and TAS-115 inhibited angiogenesis in PC-9/HGF tumors in vivo.
2.High Potency VEGFRs/MET/FMS Triple Blockade by TAS-115 Concomitantly Suppresses Tumor Progression and Bone Destruction in Tumor-Induced Bone Disease Model with Lung Carcinoma Cells.
Fujita H;Gomori A;Fujioka Y;Kataoka Y;Tanaka K;Hashimoto A;Suzuki T;Ito K;Haruma T;Yamamoto-Yokoi H;Harada N;Sakuragi M;Oda N;Matsuo K;Inada M;Yonekura K PLoS One. 2016 Oct 13;11(10):e0164830. doi: 10.1371/journal.pone.0164830. eCollection 2016.
Approximately 25-40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation.
3.New challenges and inspired answers for anticancer drug discovery and development.
Utsugi T Jpn J Clin Oncol. 2013 Oct;43(10):945-53. doi: 10.1093/jjco/hyt131. Epub 2013 Sep 5.
Many pharmaceutical companies worldwide specialize in oncology drug development and marketing. Among them, we have continued to take up the challenge of understanding the metabolism of pyrimidines as essential components of deoxyribonucleic acid for many years, and have provided unique products such as UFT(®) and TS-1 for cancer patients. Using our cumulative experience and knowledge, we are currently developing novel agents such as TAS-114, a dual inhibitor of deoxyuridine triphosphatase and dihydropyrimidine dehydrogenase, and TAS-102, a unique pyrimidine derivative inducing deoxyribonucleic acid dysfunction in cancer cells. Regarding molecular-targeted drugs, we have made huge efforts to establish ideal drug discovery platforms for the last several years. For kinase inhibitors, we established three core platforms such as a kinase-directed chemical library, a kinase assay panel and a target selection informatics system. The core platforms were further combined with peripheral technologies to measure essential parameters such as physicochemical properties, pharmacokinetics, efficacy and toxicities. Unique drug candidates have been identified at an early stage by assessing all important parameters.
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