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Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo models

Fukami, Shigemi and TOMIOKA, DAISAKU and Murakami, Yutaka and Honda, Toshiyuki and Hatakeyama, Shinji (2019) Pharmacological profiling of a dual FAK/IGF-1R kinase inhibitor TAE226 in cellular and in vivo models. BMC research notes, 12. p. 347. ISSN 1756-0500

Abstract

Objective: A dual inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor 1 receptor (IGF-1R), TAE226, was evaluated in a panel of cancer cell lines, MIA PaCa-2 human pancreatic tumor and 4T1 murine breast tumor models. The profiling data were generated during the drug discovery research prior to the first publication of TAE226 appeared in 2007 [1-3].
Results: In a panel of 37 cancer cell lines, TAE226 showed a mean GI50 value of 0.76 mole/L and was not a substrate of P-glycoprotein. In the MIA PaCa-2 model, TAE226 inhibited phosphorylation of FAK at Y397 and as IGF-1R signaling, phosphorylation of Akt at S473 in the cell culture in vitro and the tumor in vivo. Oral administration of TAE226 induced tumor stasis at 30 mg/kg and tumor regression at 100 mg/kg in the subcutaneous tumor, and inhibited the orthotopic tumor growth in a dose-dependent manner. Similarly in the 4T1 model, TAE226 inhibited phosphorylation of FAK at Y397 and Akt at S473 in the cell culture in vitro and the tumor in vivo. Oral administration of TAE226 inhibited the orthotopic tumor growth and metastasis to the lung in a dose-dependent manner. Thus, the dual FAK/IGF-1R kinase inhibitor TAE226 would be a potential therapeutic agent to prevent tumor metastasis as well as progression.

Item Type: Article
Date Deposited: 04 Jul 2019 00:45
Last Modified: 04 Jul 2019 00:45
URI: https://oak.novartis.com/id/eprint/39244

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