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

Show simple item record Deng, Wuqing Chen, Xiaojuan Jiang, Kaili Song, Xiaojuan Huang, Minhao Tu, Zheng-Chao Zhang, Zhang Lin, Xiaojing Ortega, Raquel Patterson, Adam V Smaill, Jeff B Ding, Ke Chen, Suming Chen, Yongheng Lu, Xiaoyun
dc.coverage.spatial United States 2022-05-26T03:16:03Z 2022-05-26T03:16:03Z 2021-04
dc.identifier.citation (2021). ACS Medicinal Chemistry Letters, 12(4), 647-652.
dc.identifier.issn 1948-5875
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.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 2022-04-04T20:54:53Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 33859803 (pubmed)
pubs.end-page 652
pubs.publication-status Published
dc.rights.accessrights en
pubs.subtype Journal Article
pubs.elements-id 848102 Medical and Health Sciences Science Science Research Medical Sciences Auckland Cancer Research Maurice Wilkins Centre (2010-2014)
dc.identifier.eissn 1948-5875
pubs.record-created-at-source-date 2022-04-05 2021-03-22

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