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Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

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dc.contributor.authorChan, S-
dc.contributor.authorZhang, Y-
dc.contributor.authorWang, J-
dc.contributor.authorYu, Q-
dc.contributor.authorPeng, X-
dc.contributor.authorZou, J-
dc.contributor.authorZhou, L-
dc.contributor.authorTan, L-
dc.contributor.authorDuan, Y-
dc.contributor.authorZhou, Y-
dc.contributor.authorHur, H-
dc.contributor.authorAi, J-
dc.contributor.authorWang, Z-
dc.contributor.authorRen, X-
dc.contributor.authorZhang, Z-
dc.contributor.authorDing, K-
dc.date.accessioned2023-04-20T04:36:06Z-
dc.date.available2023-04-20T04:36:06Z-
dc.date.issued2022-
dc.identifier.issn0022-2623-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/25258-
dc.description.abstractThe receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, 6li, potently inhibited AXL enzymatic activity with an IC(50) value of 1.6 nM, and tightly bound with AXL protein with a K(d) value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited AXL signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-beta1-induced epithelial-mesenchymal transition, and dose-dependently impeded cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast cancer 4T1 cells. Taken together, this study provides a new potent and selective AXL inhibitor for further anticancer drug discovery.-
dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHAntineoplastic Agents-
dc.subject.MESHBreast Neoplasms-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Proliferation-
dc.subject.MESHFemale-
dc.subject.MESHHumans-
dc.subject.MESHMice-
dc.subject.MESHProtein Kinase Inhibitors-
dc.subject.MESHPyrazoles-
dc.subject.MESHRats-
dc.subject.MESHXenograft Model Antitumor Assays-
dc.titleDiscovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors-
dc.typeArticle-
dc.identifier.pmid36358010-
dc.contributor.affiliatedAuthorHur, H-
dc.type.localJournal Papers-
dc.identifier.doi10.1021/acs.jmedchem.2c01346-
dc.citation.titleJournal of medicinal chemistry-
dc.citation.volume65-
dc.citation.number22-
dc.citation.date2022-
dc.citation.startPage15374-
dc.citation.endPage15390-
dc.identifier.bibliographicCitationJournal of medicinal chemistry, 65(22). : 15374-15390, 2022-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.identifier.eissn1520-4804-
dc.relation.journalidJ000222623-
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Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
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