PDF - 243KB, Supplementary Figure S1. Growth inhibition of TAS-115 against MET amplified cancer cell lines. Supplementary Figure S2. Kinase inhibitor-induced cell damage in rat cardiomyocytes after 96 h of treatment. Supplementary Figure S3. Gene expression changes in mice bearing human gastric cancer SC-9 after TAS-115 or sunitinib treatment. Supplementary Figure S4. Anti-tumor efficacy of TAS-115 against athymic mice transplanted with MET-amplified human gastric cancer Hs746T (A), NUGC-4 (B). Supplementary Figure S5. The inhibitory activity of sunitinib against adenosine monophosphate (AMP)-activated protein kinase (AMPK). Supplementary Table S1. Kinase inhibitory activity of TAS-115 and sunitinib against 192 kinases. Supplementary Table S2. Cell growth inhibition of TAS-115, sunitinib, sorafenib and crizotinib against MET-amplified or MET-inactivated cancer cell lines. Supplementary Table S3. Median survival times (MST) in the NUGC-4 peritoneal dissemination model after TAS-115 or sunitinib treatment.

TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.

SummaryIntroduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71–1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.

AbstractVEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 μmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer–bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685–96. ©2013 AACR.

Abstract MET is known as a proto-oncogene, which involves in growth, migration, metastasis and angiogenesis in tumor progression. Recently, it is reported that MET also functions as chemo and EGFR-TKI resistant factor in cancer cells. Particularly, HGF/MET signal seemed to reduce the potency of conventional chemotherapeutic drugs in clinical. Meanwhile, VEGF/VEGFR signal plays an important role in angiogenesis in tumor growth, and is essential for the survival signal of endothelial cells(ECs) to protect from the damage by chemotherapeutic drugs. Some VEGFR inhibitors have already been approved for the treatment of several carcinomas with monotherapy. Many clinical combination trials with VEGFR inhibitor and chemotherapeutic agents have been tried, but its therapeutic benefit are restricted. It is highly desire for improving therapeutic benefit by combination therapy with VEGFR inhibitor and standard chemotherapy. TAS-115, a novel oral MET/VEGFR dual inhibitor, demonstrated not only potent efficacy but also prominent safety profiles achieved by improvement of PK profile and cellular selectivity. Potent MET/VEGFR dual inhibition provides significant anti-tumor effect from lower dose for TAS-115. On the one hand, the improvement of PK profile and cell selectivity led to better tolerability. As a result, therapeutic window (MTD/ED50) of TAS-115 became wider than that of the pre-existing VEGFR or MET/VEGFR inhibitors. These profiles give TAS-115 the long-term dosing at full effective dose without severe toxicity. Moreover, in vitro study, HGF completely suppressed the induction of apoptosis by 5-FU or Paclitaxel in cancer cells expressed MET. Meanwhile, VEGF abolished the cytotoxic effect by these chemotherapeutic drugs against ECs. It was suggested that harmonization of both HGF and VEGF in tumor greatly contributed to the resistance against conventional chemotherapeutic drugs. The MET/VEGFR dual inhibition by TAS-115 improves the sensitivity of chemotherapeutic drugs for both cancer cells and ECs via suppression of function as chemo-resistance factor by MET and VEGFR. In fact, the combination therapies with TAS-115 and conventional chemotherapeutic drugs caused tumor regression or potent growth inhibition without sever body weight loss in several xenograft models. Notably, TAS-115 markedly enhanced anti-tumor effect of Paclitaxel, and brought tumor shrinkage of approximately 80% in the combination. More important feature is that TAS-115 has disturbed rapid tumor re-growth following Paclitaxel treatment and the higher safety profiles of TAS-115 permits combination therapy with chemotherapeutic drugs in chronic treatment. It is expected TAS-115 demonstrates prominent therapeutic benefit in combination with chemotherapy based on the synergistic action of the potent MET/VEGFR dual inhibition and higher safety profiles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1785. doi:1538-7445.AM2012-1785

Abstract The inhibition of VEGF/VEGFR has been established notable achievement as standard therapy for several cancers. However, unexpectedly success of VEGFR inhibitors (VEGFRI) has been concurrently associated with emerging new type toxicities which result in occasional patient's death and demanding high frequent rates of dose modification including dosing interruption or permanent discontinuations. Those interruptions can easily induce rapid tumor re-growth or tumor metastasis via the aggressive angiogenesis by inductions of various angiogenic factors which can confer the drug resistance to VEGFRI. These issues are considered to be main reason for no success of their combination to other chemotherapies and limiting indications. MET is a multi-functional receptor tyrosine kinase involved in various malignant phenotypes of diverse cancers. Recent studies suggest that both pathways of MET and VEGFR work in a complementary way on regulation of cancer malignant phenotypes such as angiogenesis, metastasis, or others. Therefore, their dual inhibition minimizing toxicities of VEGFRI seemed to be an attractive strategy for cancer therapy. TAS-115 is identified as a potent MET and VEGFR dual inhibitor with unique biological and pharmacokinetic properties optimized for minimized toxicities of VEGFR inhibition. In enzyme and cellular phamacodynamic assays, it potently inhibited both MET and VEGFR2 at IC50 of 10–30 nM that is equal or more potent than those of other inhibitors such as crizotinib (METI), sunitinib (VEGFRI), or foretinib (MET/VEGFRI). In cellular growth inhibition assays, it inhibited HGF/MET or VEGF dependent cellular growth at IC50 range of 10 nM. Importantly, the inhibitory effect on cellular growth was less potent under no supplementation of HGF and VEGF condition, the IC50 values were over 20 M. The selectivity between both condition is over 2000-fold while the other well-known inhibitors have only 10–100-fold selectivity. In vivo studies, orally administered TAS-115 exhibited highly potent anti-tumor activity against MET positive and negative xenografts including complete tumor eradication accompanying by abolishing of MET and VEGFR2 signal cascade. The ED50 values determined in 20 xenograft models were ranged from 3 to 25 mg/kg. The tolerability study of consecutive dosing for 4 weeks revealed no animal death incidence, even at more than 28 times higher exposure to TAS-115, which was sharp contrast to the safety of other VEGFRI including foretinib, sunitinib and sorafenib, whose therapeutic indices (MTD/ED50) were only 1.5–2. Similar safety profile was observed in rats treated for 3 weeks, its therapeutic index was more than 10, while those of other inhibitors were only 0.9–2.5 due to various severe toxicities including myelosuppression, GI, hepatic, renal injury or others. Longer term efficacy studies, for 6 weeks, revealed that this safer profile of TAS-115 resulted in prolonging time to progression much more than any other inhibitors including sunitinib or foretinib. Taken together, TAS-115 was identified as a highly potent MET/ VEGFR dual inhibitor minimized toxicities of VEGFRI, which will be expected to overcome clinical issues of previous VEGFRI or MET/VEGFRI. Its clinical trial will be initiated in this year. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A245.

Abstract c-Met is a receptor tyrosine kinase involved in various malignant phenotypes of diverse cancers. The inhibition of VEGF/VEGFR has been established as a standard therapy for several cancers. Therefore, their dual inhibition is considered to be one of most attractive strategy for cancer therapy. However, unexpectedly success of VEGFR inhibitors (VEGFRI) has been concurrently associated with emerging new type toxicities which result in occasional patient's death and requiring drug off period, frequent interruptions or dose reduction. Moreover, those interruptions resulted in a rapid tumor regrowth due to the aggressive angiogenic signaling which can confer the drug resistance to VEGFRI. These issues are considered to be main reason for the lack of success of their combination with other chemotherapeutics and the limitation of their usage. This sequence of events prompted us to develop a novel c-Met + VEGFRs dual inhibitor TAS-115, which has a high potency and prominent safety profile. A 4wks tolerability study in mice revealed no animal death even at more than 28 times higher drug exposure over the effective doses (ED50). Whereas, therapeutic index (MTD/ED50) of other VEGFRIs including foretinib, sunitinib and sorafenib were only 2-4. Similar safety profile was observed in the tox study in rats treated for 3wks, its therapeutic index was more than 10, while those of other VEGFRIs were only 0.6-2.5 due to severe toxicities. To confirm whether its better safety profile provide more benefit, longer term efficacy studies were conducted. There was no difference in efficacy within the first 2wks, however, over 2wks the animals in foretinib treatment group at MTD began to die and administration could not be continued. In contrast, TAS-115 dosing has continued for over 6wks without any toxic manifestation. The deference in their efficacies at MTD for over 4wks became greater (p<0.001). Moreover, to evaluate how the drug off period of VEGFRIs affect angiogenesis, using sunitinib as a reference, the efficacy study was done with 2wks on / 1wk off dosing regimen, mimicking its clinical setting. Although tumor growth was inhibited with 2wks consecutive dosing of sunitinib via angiogenesis inhibition, the 1wk rest caused a regrowth with recovery of vascularity. And even though its next 2wks dosing re-inhibited tumor growth, repeating these cycles allowed progressive growth with aggressive angiogenic phenotype including higher gene expressions of various angiogenic factors. Meanwhile, TAS-115 could completely inhibit tumor growth for more than 6wks via durable inhibition of angiogenesis. In addition, TAS-115 prolonged the life span in the peritoneal dissemination mouse models of human gastric cancer cell line resistant to sunitinib. Taken together, the prominent safety profile of TAS-115 can lead to more therapeutic benefit via a durable inhibition of angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3600. doi:10.1158/1538-7445.AM2011-3600

Abstract c-Met is a multi-functional proto-oncogenic receptor tyrosine kinase (RTK) involving various malignant phenotypes and aberrant expressions of HGF/c-Met axis, which are associated with poor prognosis of diverse cancers. On the other hand, VEGF/VEGFR inhibition has achieved a notable status of standard therapy for several cancers. Moreover, recent studies suggest that both RTKs work in a complementary way on cancer malignant phenotypes including angiogenesis, metastasis, and hypoxia reaction. Therefore, their dual inhibition seemed to be an attractive strategy for cancer therapy, and indeed several compounds inhibiting both targets have been subjected to clinical evaluation. However, clinical efficacy appeared to be limited so far, probably due to their poor selective of mode of action and toxicity resulting from VEGFR inhibition which result in poor tolerability restricting the dosage in the clinical setting. The optimized potent c-Met + VEGFRs dual inhibitor with better safety profile may become a successful treatment modality meeting the medical needs. To address this issue, we have developed TAS-115, a novel small molecule c-Met + VEGFRs dual inhibitor. In biochemical assay, it was identified to be a potent ATP competitive inhibitor of both c-Met and VEGFR2 at IC50 of around 10 nM that is equal or more potent than those of other known inhibitors such as crizotinib, foretinib, or sunitinib. In cellular assays, it also potently inhibited the phosophorylation of both kinases with the same potency as HGF/c-Met or VEGF dependent cellular growth at IC50 range of 10 nM. Importantly, the IC50 values under no HGF/c-Met or VEGF dependent condition were over 20,000 nM. The difference between both conditions were more than 2000-fold, while the other inhibitors showed only 10∼300 hold difference when compared to control, not stimulated cells. This selectivity was also confirmed in a panel of 40 cell lines; the IC50 values were highly correlated with HGF, c-Met mRNA expression level as revealed by coefficient value of R2&gt;0.65.In vivo studies, orally administered TAS-115 exhibited highly potent anti-tumor activity against c-Met positive and negative xenografts including complete tumor eradications accompanying by abolishing of c-Met and VEGFR2 signal cascade. The effective doses (ED50) determined in about 12 xenograft models ranged from 4 to 30 mg/kg. The tolerability study of consecutive dosing for 4 wks revealed no animal death incidence, even at more than 28 times higher exposure over the ED50 values of TAS-115, which was surprising when compared with safety of other VEGFR inhibitors including foretinib, sunitinib and sorafenib, whose therapeutic indices (MTD/ED50) were only 2∼4. Taken together, TAS-115 is a highly potent c-Met + VEGFRs dual inhibitor with prominent selectivity and safer profile indicating its therapeutic potentials in human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3577. doi:10.1158/1538-7445.AM2011-3577