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 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.