Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors.

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dc.contributor.author Deng, Wuqing
dc.contributor.author Chen, Xiaojuan
dc.contributor.author Jiang, Kaili
dc.contributor.author Song, Xiaojuan
dc.contributor.author Huang, Minhao
dc.contributor.author Tu, Zheng-Chao
dc.contributor.author Zhang, Zhang
dc.contributor.author Lin, Xiaojing
dc.contributor.author Ortega, Raquel
dc.contributor.author Patterson, Adam V
dc.contributor.author Smaill, Jeff B
dc.contributor.author Ding, Ke
dc.contributor.author Chen, Suming
dc.contributor.author Chen, Yongheng
dc.contributor.author Lu, Xiaoyun
dc.coverage.spatial United States
dc.date.accessioned 2022-05-26T03:16:03Z
dc.date.available 2022-05-26T03:16:03Z
dc.date.issued 2021-04
dc.identifier.citation (2021). ACS Medicinal Chemistry Letters, 12(4), 647-652.
dc.identifier.issn 1948-5875
dc.identifier.uri https://hdl.handle.net/2292/59508
dc.description.abstract Covalent kinase inhibitors are rapidly emerging as a class of therapeutics with clinical benefits. Herein we report a series of selective 2-aminopyrimidine-based fibroblast growth factor receptor 4 (FGFR4) inhibitors exploring different types of cysteine-targeting warheads. The structure-activity relationship study revealed that the chemically tuned warheads α-fluoro acrylamide, vinylsulfonamide, and acetaldehyde amine were suitable as covalent warheads for the design of selective FGFR4 inhibitors. Compounds <b>6a</b>, <b>6h</b>, and <b>6i</b> selectively suppressed FGFR4 enzymatic activity with IC<sub>50</sub> values of 53 ± 18, 45 ± 11, and 16 ± 4 nM, respectively, while sparing FGFR1/2/3. X-ray crystal structure and MALDI-TOF studies demonstrated that compound <b>6h</b> bearing the α-fluoro acrylamide binds to FGFR4 with an irreversible binding mode, whereas compound <b>6i</b> with an acetaldehyde amine binds to FGFR4 with a reversible covalent mode. <b>6h</b> and <b>6i</b> might provide some fundamental structural information for the rational design of new selective FGFR4 inhibitors.
dc.format.medium Electronic-eCollection
dc.language eng
dc.publisher American Chemical Society (ACS)
dc.relation.ispartofseries ACS medicinal chemistry letters
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 5.1 Pharmaceuticals
dc.subject Science & Technology
dc.subject Life Sciences & Biomedicine
dc.subject Chemistry, Medicinal
dc.subject Pharmacology & Pharmacy
dc.subject Warheads
dc.subject FGFR4
dc.subject fluoro acrylamide
dc.subject reversible covalent inhibitors
dc.subject SELECTIVITY
dc.subject 0304 Medicinal and Biomolecular Chemistry
dc.subject 0305 Organic Chemistry
dc.subject 1115 Pharmacology and Pharmaceutical Sciences
dc.title Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors.
dc.type Journal Article
dc.identifier.doi 10.1021/acsmedchemlett.1c00052
pubs.issue 4
pubs.begin-page 647
pubs.volume 12
dc.date.updated 2022-04-04T20:54:53Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 33859803 (pubmed)
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/33859803
pubs.end-page 652
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/RetrictedAccess en
pubs.subtype Journal Article
pubs.elements-id 848102
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 1948-5875
pubs.record-created-at-source-date 2022-04-05
pubs.online-publication-date 2021-03-22


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