The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis

Abstract

In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor 11b by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that 11b potently inhibited AXL expression with the IC₅₀ value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib. In the assay of antiproliferative activity on NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, 11b showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, 11b exhibited better or comparable effects to Nintedanib (tumor growth inhibition (TGI) based on tumor volume change during the trial or tumor weight). Notably, we also found that 11b prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial–mesenchymal transition (EMT) process. Another mechanism assay also proved that 11b inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.