Abstract
Abstract Transforming growth factor beta (TGFβ) signaling has been implicated in many cancers and fibrotic diseases. Recent pharmacological intervention has shown promising activities in preclinical models and early clinical trials. There are over 15 investigational agents targeting this pathway currently in the clinic, but none have been approved. In particular, small molecule TGFβ inhibitors targeting ALK5 (TGFβ type 1 receptor) have been limited by mechanism-based heart valve toxicity to low dose and intermittent dosing regimens. NEX002 is an oral liver-targeted ALK5 inhibitor with low heart exposure for the treatment of liver cancer and other gastrointestinal cancers with liver metastases. The compound was designed following drug design principles from known liver-specific drugs, such as the statins. In animals, NEX002 exerts preferential distribution (pharmacokinetic) and target inhibition (pharmacodynamic) in liver over the heart. NEX002 has demonstrated activity in several intrahepatic and subcutaneous tumor models, and significantly enhanced the durability of anti-tumor efficacy in combination with lenvatinib, a VEGFR inhibitor approved for the treatment of hepatocellular carcinoma. No heart valve toxicity was observed when benchmarked against galunisertib (systemic ALK5 inhibitor) in toxicity studies with repeated daily dosing. These data suggest that our liver-targeted/heart-sparing approach may allow more robust target engagement compared to systemic ALK5 inhibitors through higher dose or more frequent dosing. Citation Format: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu. Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1661.
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