Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.
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Date
2018-08-23Author
Hudson, L
Mui, J
Vázquez, S
Carvalho, DM
Williams, E
Jones, C
Bullock, AN
Hoelder, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line
Humans
Activin Receptors, Type I
Protein Kinase Inhibitors
Crystallography, X-Ray
Drug Evaluation, Preclinical
Structure-Activity Relationship
Dose-Response Relationship, Drug
Quinazolinones
Research team
Medicinal Chemistry 4 (including Analytical Chemistry)
Glioma Team
Language
eng
Date accepted
2018-08-07
License start date
2018-08-07
Citation
Journal of medicinal chemistry, 2018, 61 (16), pp. 7261 - 7272
Publisher
AMER CHEMICAL SOC