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

In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor <b>11b</b> by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that <b>11b</b> 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, <b>11b</b> showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, <b>11b</b> 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 <b>11b</b> prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial-mesenchymal transition (EMT) process. Another mechanism assay also proved that <b>11b</b> inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.