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

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dc.contributor.author Shao, Min
dc.contributor.author Chen, Xiaojuan
dc.contributor.author Yang, Fang
dc.contributor.author Song, Xiaojuan
dc.contributor.author Zhou, Yang
dc.contributor.author Lin, Qianmeng
dc.contributor.author Fu, Ying
dc.contributor.author Ortega, Raquel
dc.contributor.author Lin, Xiaojing
dc.contributor.author Tu, Zhengchao
dc.contributor.author Patterson, Adam V
dc.contributor.author Smaill, Jeff B
dc.contributor.author Chen, Yongheng
dc.contributor.author Lu, Xiaoyun
dc.coverage.spatial United States
dc.date.accessioned 2022-05-24T22:19:47Z
dc.date.available 2022-05-24T22:19:47Z
dc.date.issued 2022-03-10
dc.identifier.citation (2022). Journal of Medicinal Chemistry, 65(6), 5113-5133.
dc.identifier.issn 0022-2623
dc.identifier.uri https://hdl.handle.net/2292/59488
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.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm
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
dc.date.updated 2022-04-04T20:53:25Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 35271262 (pubmed)
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/35271262
pubs.end-page 5133
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/RetrictedAccess en
pubs.subtype Journal Article
pubs.elements-id 889608
pubs.org-id Medical and Health Sciences
pubs.org-id Science
pubs.org-id Science Research
pubs.org-id Medical Sciences
pubs.org-id Auckland Cancer Research
pubs.org-id Maurice Wilkins Centre (2010-2014)
dc.identifier.eissn 1520-4804
pubs.record-created-at-source-date 2022-04-05
pubs.online-publication-date 2022-03-10


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