Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.
Loading...
Embargo End Date
ICR Authors
Authors
Hudson, L
Mui, J
Vázquez, S
Carvalho, DM
Williams, E
Jones, C
Bullock, AN
Hoelder, S
Mui, J
Vázquez, S
Carvalho, DM
Williams, E
Jones, C
Bullock, AN
Hoelder, S
Document Type
Journal Article
Date
2018-08-23
Date Accepted
2018-08-07
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.
Citation
Journal of medicinal chemistry, 2018, 61 (16), pp. 7261 - 7272
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Collections
Research Team
Medicinal Chemistry 4 (including Analytical Chemistry)
Glioma Team
Glioma Team