Abstract
e16741 Background: Owing to its high mortality and lack of effective treatments, there is therefore an urgent unmet need to develop novel and more effective treatments for pancreatic cancer (PC). ABP-1119 is a novel and potent multi-TRK Inhibitor for several PC-related prime tyrosine kinases (TRKs), such as EGFR, HER2, ALK, and BTK. Pre-clinical studies with ABP-1119, especially study to evaluate its tumor growth inhibition activity on pancreatic tumor xenograft model, are planned. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, ALK, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of Mia-Paca-2 Cell Line, (3) Anti-tumor inhibition study of ABP-1119 with the pancreatic cancer nude mice, (4) Safety studies of ABP-1119 for Ames, hERG, and maximum tolerated dose (MTD). Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1119 was 0.9nM to EGFR, 4.8nM to HER2, 0.9nM to ALK, and 2.1nM to BTK, respectively. Its inhibition activity for Cell Line Mia-Paca-2 was 0.06 µM. In anti-tumor inhibition study with the Mia-Paca-2 tumor nude mice for 14 days, the anti-tumor inhibition rate of ABP-1119 (50 mg/kg, QD) was over 82% (vs Erlotinib as a positive control, 50mg/kg, QD, inhibition rate: 48%), and no any death and other serious side effects were observed during the nude mice tests. Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in MTD studies with ABP-1119 (100mg/kg, QD) for 14 days. ABP-1119 also had very good metabolic stability in Human (T1/2 = 2.5hr). Conclusions: Based on our completed preclinical study results, ABP-1119 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and good tumor growth inhibition activity with tolerable toxicity in pancreatic tumor xenograft in nude mice model. It is warranted to continue further investigation in pancreatic cancer.
Published Version
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