Structural optimization of Imidazo[1, 2-a]pyridine derivatives for the treatment of gastric cancer via STAT3 signaling pathway
- Eur J Med Chem. 2022 Dec 15:244:114858. doi: 10.1016/j.ejmech.2022.114858.
- 1. Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
- 2. Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
- 3. Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
- 4. Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
- 5. Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: [email protected].
- 6. Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address: [email protected].
STAT3 is a promising therapeutic target for the treatment of gastric Cancer, which is one of the most common solid tumors worldwide. In the previous works, we discovered a series of novel STAT3 inhibitors bearing an imidazo[1,2-a] pyridine scaffold. In order to improve the metabolic stability of these compounds, herein we performed a systematic structural optimization leading to a bioactive inhibitor 42, which demonstrated significant effects on inhibiting the growth, migration and invasion of human gastric Cancer cells lines (AGS and MGC-803). Meanwhile, it was able to block the phosphorylation and dimerization of STAT3 at low micromolar concentration. Furthermore, compound 42 obviously suppressed tumor growth in MGC-803 derived xenograft mouse model, suggesting that it deserves further exploration as a promising anti-cancer agent for advanced gastric Cancer.