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J Med Chem. 2018 Aug 23;61(16):7261-7272. doi: 10.1021/acs.jmedchem.8b00782. Epub 2018 Aug 7.

Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.

Author information

1
Institute of Cancer Research , 15 Cotswold Road , Sutton , Surrey SM2 5NG , United Kingdom.
2
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB) , Universitat de Barcelona , Av. Joan XXIII s/n , Barcelona E-08028 , Spain.
3
Structural Genomics Consortium , University of Oxford , Old Road Campus Research Building, Roosevelt Drive , Oxford OX3 7DQ , United Kingdom.

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.

PMID:
30085668
PMCID:
PMC6109843
DOI:
10.1021/acs.jmedchem.8b00782
[Indexed for MEDLINE]
Free PMC Article

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