Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase

Abstract

Receptor tyrosine kinase AXL exerts pivotal roles in cancer cell survival, metastasis, and drug resistance. Pharmacologic or genetic targeting of the aberrant AXL signaling has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive antitumor drug target. By conformational restriction of the anilinopyrimidine 10e and systematic structure−activity relationship (SAR) exploration, we discovered 10H-benzo[b]pyrido[2,3-e][1,4]oxazine 16j as a potent and orally bioavailable AXL inhibitor. As a type II AXL inhibitor, compound 16j displayed about 15-fold selectivity for AXL over its highly homologous kinase c-Met. And it significantly blocked cellular AXL signaling, inhibited AXL-mediated cell proliferation, and impaired growth arrest-specific protein 6 (Gas6)/AXL-stimulated cell migration and invasion. Moreover, 16j exhibited significant antitumor efficacy in AXL-driven xenograft model at a well-tolerant dosage, causing tumor stasis or regression.

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

“…1 H NMR (600 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 8.58 (dd, J = 7.2, 2.4 Hz, 1H), 8.50 (s, 1H), 8.10 (dd, J = 6.6, 2.4 Hz, 1H), 7.91 (dd, J = 3.0, 1.2 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62 (dd, J = 5.4, 3.0 Hz, 1H), 7.61 (dd, J = 9.0, 4.8 Hz, 2H), 7.42 (dd, J = 9.0, 8.4 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 7.13 (dd, J = 8.1, 7.5 Hz, 1H),7.08 (dd, J = 5.4, 1.2 Hz, 1H), 6.79 (dd, J = 2.1, 1.8 Hz, 1H), 6.73 (ddd, J = 7.5, 1.8, 1.2 Hz, 1H), 6.71 (dd, J = 7.2, 6.6 Hz, 1H), 6.63 (ddd, J = 8.1, 2.1, 1.2 Hz, 1H), 5.22 (s, 2H). 13 (29). To a solution of 56 (76 mg, 0.13 mmol, 1.0 equiv) in N,Ndimethylformamide (2.5 mL) and tetrahydrofuran (2.5 mL) were added N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (44 mg, 0.19 mmol, 1.5 equiv), Pd(dppf)Cl 2 (19 mg, 0.03 mmol, 21 mol %), and 2 M Na 2 CO 3(aq) (0.3 mL, 4.0 equiv).…”

“…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.…”