Abstract B186: ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers and is also a leading cause of cancer-related deaths worldwide. Until now, treatments for HCC remain limited, especially for the shortage of promising systemic therapies to replace systemic chemotherapy. Sorafenib, the first drug applied in targeted therapy for HCC, was approved and drew considerable attention. However, the efficacy and side effects of sorafenib are still unsatisfied, which make sorafenib far from ideal for treatment of HCC. Thus, developing novel therapeutics for HCC is necessary. A novel compound, ITRI-2531, is developed to improve the efficacy from sorafenib. ITRI-2531 shows cytotoxicity in HCC cell lines (Huh-7 and PLC/PRF/5) and patient-derived HCC tissue cell lines. In studies of kinase activities, ITRI-2531 suppresses the phosphorylation of MEK and ERK in PLC/PRF/5 cells and shows inhibition of multiple kinases (FLT3, FLT4, PDGFRA, PGDFRB, and VEGFR2) in KINOMEscanTM study. In in vivo studies, oral treatment of ITRI-2531 repressed subcutaneous Huh-7 and PLC/PRF/5 tumor growth in severe combined immunodeficient (SCID) mice and shows better efficacy than sorafinib. Moreover, ITRI-2531 prolongs the survival of SCID mice with orthotopic patient-derived xenograft tumor and suppresses alpha-fetoprotein in serum. On the other hand, ITRI-2531 also has good pharmacokinetic profiles. According to these results, we believe that ITRI-2531 warrants further evaluation as a new anti-HCC drug. Citation Format: Tsung-Keng Kuo, On Lee, Mai-Wei Lin, Li-Zong Lin, Chun-Min Liu, Tai-ju Hsieh, Chun-Chung Wang, Shyh-Horng Lin, Chia-Ni Chang, Hui-Chun Hsu, Nien-Tzu Chou, Chin-Pen Lai, Chih-Hung Chen, Chia-Mu Tu, Shih-Ta Chen, Yuan-Jang Tsai, Chih-Peng Liu, Jenn-Tsang Hwang, Jui-Wen Huang, Yen-Chun Chen, Chrong-Shiong Hwang, Hsiang-Wen Tseng. ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B186.