Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.

Show simple item record Shao, Min Chen, Xiaojuan Yang, Fang Song, Xiaojuan Zhou, Yang Lin, Qianmeng Fu, Ying Ortega, Raquel Lin, Xiaojing Tu, Zhengchao Patterson, Adam V Smaill, Jeff B Chen, Yongheng Lu, Xiaoyun
dc.coverage.spatial United States 2022-05-24T22:19:47Z 2022-05-24T22:19:47Z 2022-03-10
dc.identifier.citation (2022). Journal of Medicinal Chemistry, 65(6), 5113-5133.
dc.identifier.issn 0022-2623
dc.description.abstract Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (<b>7v</b>) exhibited excellent potency against FGFR4, FGFR4<sup>V550L</sup>, and FGFR4<sup>V550M</sup> with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound <b>7v</b> demonstrated modest <i>in vivo</i> antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.
dc.format.medium Print-Electronic
dc.language eng
dc.publisher American Chemical Society (ACS)
dc.relation.ispartofseries Journal of medicinal chemistry
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.subject Cancer
dc.subject Liver Disease
dc.subject Liver Cancer
dc.subject Digestive Diseases
dc.subject Rare Diseases
dc.subject 5.1 Pharmaceuticals
dc.subject 0304 Medicinal and Biomolecular Chemistry
dc.subject 0305 Organic Chemistry
dc.subject 1115 Pharmacology and Pharmaceutical Sciences
dc.title Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.
dc.type Journal Article
dc.identifier.doi 10.1021/acs.jmedchem.2c00096
pubs.issue 6
pubs.begin-page 5113
pubs.volume 65 2022-04-04T20:53:25Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 35271262 (pubmed)
pubs.end-page 5133
pubs.publication-status Published
dc.rights.accessrights en
pubs.subtype Journal Article
pubs.elements-id 889608 Medical and Health Sciences Science Science Research Medical Sciences Auckland Cancer Research Maurice Wilkins Centre (2010-2014)
dc.identifier.eissn 1520-4804
pubs.record-created-at-source-date 2022-04-05 2022-03-10

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