Discovery of a potent and selective Axl inhibitor in preclinical model

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment

“…For 27: 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.00 (s, 1H), 8.60 (dd, J = 7.5, 1.8 Hz, 1H), 8.45 (s, 1H), 8.35 (s, 2H), 8.12 (dd, J = 6.6, 1.8 Hz, 1H), 8.02 (s, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.62 (dd, J = 9.0, 4.8 Hz, 2H), 7.43 (dd, J = 9.0, 8.4 Hz, 2H), 7.30 (d, J = 9.0 Hz, 2H), 7.13 (s, 1H), 6.73 (dd, J = 7.5, 6.6 Hz, 1H), 3.92 (s, 3H). 13 (28). To a solution of 22 (32 mg, 0.05 mmol, 1.0 equiv) in dichloromethane (1.0 mL) were added triethylamine (30 μL, 0.22 mmol, 4.1 equiv) and acetyl chloride (12 μL, 0.17 mmol, 3.2 equiv), and then, the reaction mixture was stirred at room temperature.…”

“…The reaction mixture was degassed for 30 min, refilled with Argon (g) , and stirred at 110 °C. After stirring for 12 h, the reaction mixture was cooled down to room temperature, filtered through Celite, added with water (10 mL), and extracted into CH 2 Cl 2 (10 mL × 3), The (28). To a solution of 22 (32 mg, 0.05 mmol, 1.0 equiv) in dichloromethane (1.0 mL) were added triethylamine (30 μL, 0.22 mmol, 4.1 equiv) and acetyl chloride (12 μL, 0.17 mmol, 3.2 equiv), and then, the reaction mixture was stirred at room temperature.…”

“…Several multitargeting MET inhibitors have shown strong inhibitory abilities against MER and AXL, including glesatinib ( 5 ), cabozantinib ( 6 ), and others with nanomolar-level IC 50 values (Figure ). − Notably, merestinib (LY2801653, 7 ) and tamnorzatinib (ONO-7475, 8 ), identified as highly potent dual MER/AXL inhibitors, also behaved strong inhibitory abilities against MET protein. , In addition to the aforementioned clinical candidates, numerous MER-selective, AXL-selective, or dual MER/AXL inhibitors are currently under study at various stages of development. − …”

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

“…However, Cabozantinib is not a selective AXL inhibitor, and it has very strong inhibitory activities against multiple kinases including VEGFR2, c-Met, KIT, FLT3, etc., which may lead to some potential toxicities and side effects. Some similar derivatives, such as BMS-777607 ( 3 ) 40 , compounds 4 – 6 41 , 42 , 43 and other reported AXL inhibitors 31 , 32 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , have been in different stages of preclinical and clinical trials for various cancer indications. In view of the importance of AXL in tumorigenesis and progression, the development of selective AXL inhibitors is of great significance for the clinical treatment of tumors.…”