A novel flavonoid derivative for treating colorectal cancer by suppressing tumor angiogenesis through VEGFR2 inhibition.
INTRODUCTION Inhibiting tumor angiogenesis is a recognized anticancer strategy. VEGFR2 is a key driver of pathological angiogenesis via VEGF signaling. Natural chalcones can target VEGFR2 but are limited by weak activity and low yield. OBJECTIVE To design and synthesize novel chalcones as VEGFR2 inhibitors to suppress tumor angiogenesis, thereby offering a new anti-angiogenic strategy for colorectal cancer (CRC). METHODS A series of novel chalcones was synthesized, and compound 27j, bearing a bis-Michael acceptor moiety, was selected. Its binding affinity to VEGFR2 was assessed by surface plasmon resonance (SPR), and a kinase selectivity profile was generated. The effects on VEGFR2 activation and downstream signaling pathways were analyzed. Anti-angiogenic effects and inhibition of CRC growth were evaluated through in vitro experiments, in vivo animal studies, and patient-derived xenograft (PDX) models. Pharmacokinetics, ADME, and acute/chronic toxicity were characterized. RESULTS Compound 27j demonstrated some binding affinity for VEGFR2 in SPR assays. However, it did not exhibit significant inhibitory activity in enzymatic kinase assays, suggesting that its mechanism of action may differ from classical ATP competition. In vitro and in vivo studies confirmed that 27j effectively inhibits key angiogenetic processes and interferes with VEGFR2 activation and its downstream signaling. In PDX models, angiogenesis was inhibited in tumors from the 27j-treated group, and there was a trend toward delayed CRC growth. CONCLUSION Compound 27j represents a novel VEGFR2 inhibitor whose mechanism may involve non-classical rather than direct ATP competition. It exhibits promising anti-angiogenic and anti-tumor activity in CRC models, supporting its further investigation as a promising lead compound for anti-tumor angiogenesis therapy.