The Discovery\nof a Novel AXL/Triple Angiokinase Inhibitor\nBased on 6‑Chloro-Substituted Indolinone and Side Chain Methyl\nSubstitution Inhibiting Pancreatic Cancer Growth and Metastasis

In\nthis study, we discovered and identified a novel AXL/triple\nangiokinase inhibitor <b>11b</b> by rational structural modification\nbased on the structure of triple angiokinase inhibitor Nintedanib.\nWe found that <b>11b</b> potently inhibited AXL expression with\nthe IC<sub>50</sub> value of 3.75 nM and possessed similar inhibitory\nactivity on KDR as Nintedanib. In the assay of antiproliferative activity\non NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, <b>11b</b> showed\nbetter inhibitory ability than Nintedanib. In pancreatic cancer xenograft\nmouse models from Bxpc-3 cells, even when the dosage was halved, <b>11b</b> exhibited better or comparable effects to Nintedanib (tumor\ngrowth inhibition (TGI) based on tumor volume change during the trial\nor tumor weight). Notably, we also found that <b>11b</b> prohibited\nBxpc-3 resulted lung metastasis by inhibiting its epithelial–mesenchymal\ntransition (EMT) process. Another mechanism assay also proved that <b>11b</b> inhibited the function of blood vessels and fibroblasts,\npromoted apoptosis of cancer and fibroblast cells, and exhibited low\ntoxicity and good metabolic stability.