{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["13(12)"],"submitter":["Fang F"],"pubmed_abstract":["As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound <b>59</b> showed a desirable AXL kinase inhibitory activity (IC<sub>50</sub>: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound <b>59</b> could potently inhibit BaF3/TEL-AXL cell viability (IC<sub>50</sub>: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound <b>59</b> oral administration showed good pharmacokinetic profile and <i>in vivo</i> antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development."],"journal":["Acta pharmaceutica Sinica. B"],"pagination":["4918-4933"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10692477"],"repository":["biostudies-literature"],"pubmed_title":["Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors."],"pmcid":["PMC10692477"],"pubmed_authors":["Peng X","Liu H","Li J","Zhang D","Li C","Liang X","Fang F","Wang D","Wang H","Zhou Y","Ai J","Dai Y","Zhao Y","Geng M","Li Y","Ji Y"],"additional_accession":[]},"is_claimable":false,"name":"Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors.","description":"As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound <b>59</b> showed a desirable AXL kinase inhibitory activity (IC<sub>50</sub>: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound <b>59</b> could potently inhibit BaF3/TEL-AXL cell viability (IC<sub>50</sub>: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound <b>59</b> oral administration showed good pharmacokinetic profile and <i>in vivo</i> antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Dec","modification":"2026-05-28T23:52:43.657Z","creation":"2025-04-04T14:18:58.232Z"},"accession":"S-EPMC10692477","cross_references":{"pubmed":["38045061"],"doi":["10.1016/j.apsb.2023.10.002"]}}