Abstract 3577: TAS-115: a highly potent c-Met + VEGFRs dual inhibitor with prominently safer profile

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>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

New Challenges and Inspired Answers for Anticancer Drug Discovery and Development

“…At first, this approach was employed to explore ATP-binding pockets of target kinases and developed two ATP-competitive inhibitors: TAS-115, a dual inhibitor of c-Met and vascular endothelial growth factor-receptor tyrosine kinase (RTK) (25–27), and TAS-2104, a selective Aurora A inhibitor (28,29). …”