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Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept

Abstract:
Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.
Publication status:
Published
Peer review status:
Peer reviewed
Version:
Publisher's Version

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Publisher copy:
10.1021/acs.jmedchem.8b00782

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ORCID:
0000-0002-9296-6026
Carvalho, DM More by this author
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Institution:
University of Oxford
Division:
Medical Sciences Division
Department:
NDM
Subgroup:
Structural Genomics Consortium
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National Health Service More from this funder
Publisher:
American Chemical Society Publisher's website
Journal:
Journal of Medicinal Chemistry Journal website
Volume:
61
Issue:
16
Pages:
7261-7272
Publication date:
2018-08-07
Acceptance date:
2018-07-13
DOI:
EISSN:
1520-4804
ISSN:
0022-2623
Pubs id:
pubs:905018
URN:
uri:2c2138f9-a59d-449b-a9cd-733d406aaea5
UUID:
uuid:2c2138f9-a59d-449b-a9cd-733d406aaea5
Local pid:
pubs:905018
Language:
English
Keywords:

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