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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.

Original publication




Journal article


J Med Chem

Publication Date





7261 - 7272


Activin Receptors, Type I, Cell Line, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Protein Kinase Inhibitors, Quinazolinones, Structure-Activity Relationship