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IC50 values for the inhibition of 93 human kinases by E7090.

IC50 values for growth inhibition of various cancer cell lines by E7090.

Western blot analysis of FGFR1 in human lung cancer cell lines harboring FGFR1 amplifications.

Kinome map of E7090. IC50 values of E7090 against wild-type kinases were used to create this kinome map. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).

Inhibition of expression of proteins downstream of FGFR, including FRS2α, ERK, and AKT, in SNU-16 cells in vitro.

Western blot analysis of phospho-FGFR in SNU-16 tumors at the indicated times after treatment with the indicated concentrations of E7090. See also Figure 3D.

siRNA knockdown experiment in 4T1 cells indicating that growth of 4T1 breast cancer cells depends on FGFR2 and FGFR3.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630–9. ©2016 AACR.

Supplementary Table legends and Supplementary Figure legends.

Introduction The objective of this study was to evaluate the efficacy and safety of eribulin monotherapy, relative to vinorelbine, in Chinese women with locally recurrent/metastatic breast cancer (MBC). Methods This phase III open-label, randomised, parallel-group, multicentre clinical trial enrolled patients with locally recurrent or MBC who had had 2–5 prior chemotherapy regimens, including an anthracycline and taxane) from September 26, 2013, to May 19, 2015. Women were randomised 1:1 to receive eribulin (1.4 mg/m2, intravenously, on day 1 and day 8) or vinorelbine (25 mg/m2, intravenously, on day 1, day 8 and day 15) every 21 days. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), duration of response and overall survival (OS). Results Five hundred thirty women were randomised to receive eribulin (n = 264) or vinorelbine (n = 266). Improvement in PFS was observed with eribulin compared with vinorelbine (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.65–0.98, P = 0.036); median PFS was 2.8 months in both treatment arms. The median OS was 13.4 months with eribulin and 12.5 months with vinorelbine (HR: 1.03, 95% CI: 0.80–1.31, P = 0.838). The ORR was 30.7% (95% CI: 25.2%–36.6%) with eribulin and 16.9% (95% CI: 12.6%–22.0%) with vinorelbine (P Conclusions Eribulin achieved statistically significantly superior PFS (and response rate) compared with vinorelbine in previously treated women with locally recurrent or MBC. Eribulin appeared to be better tolerated than vinorelbine, with no new safety signals observed. Trial registration National Institutes of Health ClinicalTrials.gov registry, NCT02225470. Registered 05 August 2014- Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT02225470?term=NCT02225470&rank=1 .

538 Background: E7090 is a selective tyrosine kinase inhibitor against FGFR1-3. This first-in-human phase I study has been conducted in Japan and consists of 2 parts. Based on the toxic, pharmacokinetic, and pharmacodynamic profiles in Part 1, dose escalation study, the recommended dose was determined to be 140 mg QD for Part 2, an expansion study part restricted to patients with tumors harboring FGFR gene alterations. Here we provide the interim analysis results of Part 2. Methods: In Part 2, patients with cholangiocarcinoma harboring FGFR2 gene fusion (CCA cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Patients received oral dosing of E7090 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by site investigators using RECIST 1.1. Results: As of 31 March 2019, 16 patients including 6 patients in CCA cohort and 10 patients in GC cohort received E7090 in Part2. Median age was 63 years, 25% were female, ECOG PS of 0 and 1 were 50% respectively. 5 patients (83%) in CCA cohort and 1 patient (10%) in GC cohort achieved partial response as the best overall response. The disease control rates were 100% in CCA cohort and 30% in GC cohort, respectively. Median progression-free survivals were 8.3 months in CCA cohort and 2.8 months in GC cohort at the cut-off date. 2 patients with CCA remain on treatment. The most common treatment-related TEAEs occurring in 30% or more of patients in Part 2 were hyperphosphatemia (100%), palmar–plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (38%), stomatitis (31%), diarrhea (31%), increased AST (31%) and blood creatinine increased (31%). Grade≥3 treatment-related TEAEs were reported in 2 out of 16 patients (13%); they were increased AST, lipase increased and retinopathy. Conclusions: This study indicated that E7090 has a manageable safety profile in Part 2 and the promising clinical activity in CCA patients with FGFR2 gene fusion.

Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630–9. ©2016 AACR.

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1α overexpression has been associated with poor prognosis in patients with various types of cancer. Here, we describe ER-400583-00 as a novel HIF-1 inhibitor. ER-400583-00 suppressed the production of HIF-1α protein in response to hypoxia, with a half-maximal inhibitory concentration value of 3.7 nM in human U251 glioma cells. The oral administration of 100 mg/kg ER-400583-00 to mice bearing U251 tumor xenografts resulted in a rapid suppression of HIF-1α that persisted for 24 h. Immunohistochemical analysis revealed that ER-400583-00 suppressed the proliferation of cancer cells most prominently in areas distal to the region of blood perfusion, where HIF-1α-expressing hypoxic cancer cells were located. These hypoxic cancer cells were resistant to radiation therapy. ER-400583-00 showed a synergistic interaction with radiation therapy in terms of antitumor activity. These data suggest that HIF-1 blockade by small compounds may have therapeutic value in cancer, especially in combination with radiation therapy.

A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (...

A novel and efficient glycosyl donor having a p-trifluoromethylbenzylthio-N-p-trifluoromethylphenylformimidate group at an anomeric position is easily prepared by the addition of anomeric hydroxy group of 2,3,4,6-tetra-O-benzyl-α,β-D-glucopyranose to p-trifluoromethylphenyl isothiocyanate, followed by treatment with p-trifluoromethylbenzyl bromide. Catalytic and stereoselective glycosylation of various glycosyl acceptors with the above glycosyl donor smoothly proceeds by using various protic and Lewis acid catalysts which interact with its nitrogen atom. Further, catalytic and highly 1,2-cis or 1,2-trans stereoselective and chemoselective glycosylation between two different “armed” and “disarmed” glycosyl p-trifluoromethylbenzylthio-N-p-trifluoromethylphenylformimidates is also performed effectively in the presence of a catalytic amount of trifluoromethanesulfonic acid (TfOH) at −78 °C in tBuOMe or EtCN, respectively. These glycosylations are applied to successful one-pot sequential syntheses of trisaccha...

Reduction of dithioacetals derived from aromatic aldehydes with low valent titanium iodide species in situ formed by treatment of titanium(IV) iodide with zinc in a mixed solvent of dichloro-methane and pivalonitrile at room temperature afforded coupling products, vicinal bis(alkylthio) derivatives, in good to high yields.

A novel and efficient glycosyl donor having a p-trifluoro-methylbenzylthio-p-trifluoromethylphenyl formimidate function as a leaving group is easily prepared by the addition of anomeric hydroxyl group of 2,3,4,6-tetra-O-benzoyl-α,β-D-glucopyranose to p-trifluoromethylphenyl isothiocyanate, followed by treatment with p-trifluoromethylbenzyl bromide. Catalytic and stereoselective glycosylation using this glycosyl donor effectively proceeds by activating its nitorogen atom with various protic and Lewis acids.

Catalytic and chemoselective glycosylation between novel “armed” and “disarmed” glycosyl p-trifluoromethylbenzylthio-p-trifluoromethylphenyl formimidates was effectively performed in the presence o...

c-Met is the cellular receptor for hepatocyte growth factor (HGF) and is known to be dysregulated in various types of human cancers. Activation of the HGF/c-Met pathway causes tumor progression, invasion, and metastasis. Vascular endothelial growth factor (VEGF) is also known as a key molecule in tumor progression through the induction of tumor angiogenesis. Because of their key roles in tumor progression, these pathways provide attractive targets for therapeutic intervention. We have generated a novel, orally active, small molecule compound, E7050, which inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2. In vitro studies indicate that E7050 potently inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In vivo studies using E7050 showed inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors, and strong inhibition of tumor growth and tumor angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of E7050 (50-200 mg/kg) induced tumor regression and disappearance. In a peritoneal dissemination model, E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. Our results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer.

The use of pyridine-3-sulfonyl chloride (3-PSC) in dehydrating condensation was investigated. This novel reagent was successfully employed as a mild dehydrating reagent for preparing various carbox...

A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (...

A highly efficient method by using benzenesulfonic anhydride (BSA) in the presence of 4-(dimethylamino)pyridine (DMAP) to synthesize carboxamides from various carboxylic acids and amines including ...

A highly useful method for the preparation of carboxamides from various carboxylic acids and amines is established by using pyridine-3-carboxylic anhydride (3-PCA) in the presence of 4-(dimethylami...

A synthesis of carboxylic esters from various carboxylic acids and alcohols is successfully carried out by using a condensation reagent, pyridine-3-carboxylic anhydride (3-PCA). This reaction mater...

The fibroblast growth factor (FGF) signaling pathway comprises 18 ligands and 4 FGF receptor subtypes, FGFR1, 2, 3 and 4, which are known as receptor-type tyrosine kinases corresponding to those ligands. Upon ligand binding, FGFRs activate an array of downstream signaling pathways, such as the mitogen activated protein kinase (MAPK) and the phosphoinositide-3-kinase (PI3K)/Akt pathways. Genetic abnormalities (gene fusion, mutation and amplification) of FGFRs are known to cause constitutive activation of their signaling pathways, which play an important role in proliferation, survival and migration of cancer cells, tumor angiogenesis, drug resistance, etc. These abnormalities have also been reported to be involved in different cancer types including lung, breast, endometrial, gastric, and bladder cancer so far. Therefore, FGFRs are considered as one of potential targets for cancer therapy. E7090 is an orally available, selective and potent inhibitor of FGFR1, 2 and 3 tyrosine kinase activities. E7090 displayed inhibition of FGFR1, 2, and 3 kinase activities with the IC50 values of approximately 1 nmol/L. E7090 also inhibited the growth of SNU-16, human gastric cancer cell line harboring FGFR2 amplification with an IC50 value of 3 nmol/L. This activity was about 60-fold stronger than that against VEGF-stimulated HUVEC growth. Kinase profiling assay consisting of 93 kinases including non-receptor and serine/threonine kinases, also demonstrated that E7090 inhibited limited kinases including FGFR-1, -2 and -3. In addition, E7090 inhibited proliferation of human cancer cell lines harboring various types of FGFRs gene abnormalities such as amplification, mutation, or translocation in vitro, which are confirmed by the inhibition of FGFR signaling. E7090 also showed significant antitumor activities on various human xenografts harboring FGFRs gene abnormalities in a dose dependent manner and demonstrated tumor shrinkage at several doses in some models. Furthermore, pharmacodynamics analysis revealed that E7090 inhibited phosphorylation of FGFRs in SNU-16 xenograft tumors in a dose-dependent manner. Overall, the in vitro and in vivo studies confirm that E7090 is a potent and selective FGFRs inhibitor, showing promising antitumor activities with wider therapeutic windows in preclinical cancer models harboring FGFRs gene abnormalities. E7090 has been advanced through preclinical development and we disclose here the first details of its preclinical profile. Citation Format: Saori Watanabe Miyano, Yuji Yamamoto, Kotaro Kodama, Setsuo Funasaka, Satoshi Nagao, Naoko Hata Sugi, Hiroko Kuramochi, Katsuyuki Ishikawa, Kiyoshi Okamoto, Yukinori Minoshima, Takayuki Nakagawa, Yusuke Nakatani, Yuki Karoji, Isao Ohashi, Yoshinobu Yamane, Keigo Tanaka, Toshimi Okada, Tomohiro Matsushima, Junji Matsui, Masao Iwata, Akihiko Tsuruoka, Toshimitsu Uenaka. E7090: A potent and selective FGFR inhibitor with activity in multiple FGFR-driven cancer models with distinct mechanisms of activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 770. doi:10.1158/1538-7445.AM2015-770

The use of pyridine-3-sulfonyl chloride (3-PSC) in dehydrating condensation was investigated. This novel reagent was successfully employed as a mild dehydrating reagent for preparing various carbox...

A highly efficient method by using benzenesulfonic anhydride (BSA) in the presence of 4-(dimethylamino)pyridine (DMAP) to synthesize carboxamides from various carboxylic acids and amines including ...

Catalytic and chemoselective glycosylation between novel “armed” and “disarmed” glycosyl p-trifluoromethylbenzylthio-p-trifluoromethylphenyl formimidates was effectively performed in the presence o...

A novel and efficient glycosyl donor having a p-trifluoro-methylbenzylthio-p-trifluoromethylphenyl formimidate function as a leaving group is easily prepared by the addition of anomeric hydroxyl group of 2,3,4,6-tetra-O-benzoyl-α,β-D-glucopyranose to p-trifluoromethylphenyl isothiocyanate, followed by treatment with p-trifluoromethylbenzyl bromide. Catalytic and stereoselective glycosylation using this glycosyl donor effectively proceeds by activating its nitorogen atom with various protic and Lewis acids.

Reduction of dithioacetals derived from aromatic aldehydes with low valent titanium iodide species in situ formed by treatment of titanium(IV) iodide with zinc in a mixed solvent of dichloro-methane and pivalonitrile at room temperature afforded coupling products, vicinal bis(alkylthio) derivatives, in good to high yields.