Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept
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 th...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2018
|
| _version_ | 1826264941920780288 |
|---|---|
| author | Hudson, L Mui, J Vázquez, S Carvalho, D Williams, E Jones, C Bullock, A Hoelder, S |
| author_facet | Hudson, L Mui, J Vázquez, S Carvalho, D Williams, E Jones, C Bullock, A Hoelder, S |
| author_sort | Hudson, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:15:53Z |
| format | Journal article |
| id | oxford-uuid:2c2138f9-a59d-449b-a9cd-733d406aaea5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:15:53Z |
| publishDate | 2018 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:2c2138f9-a59d-449b-a9cd-733d406aaea52022-03-26T12:35:06ZNovel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of conceptJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2c2138f9-a59d-449b-a9cd-733d406aaea5EnglishSymplectic Elements at OxfordAmerican Chemical Society2018Hudson, LMui, JVázquez, SCarvalho, DWilliams, EJones, CBullock, AHoelder, SStructure-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. |
| spellingShingle | Hudson, L Mui, J Vázquez, S Carvalho, D Williams, E Jones, C Bullock, A Hoelder, S Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title | Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title_full | Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title_fullStr | Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title_full_unstemmed | Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title_short | Novel Quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure-activity relationship, structural characterization, Kinase profiling, and cellular proof of concept |
| title_sort | novel quinazolinone inhibitors of alk2 flip between alternate binding modes structure activity relationship structural characterization kinase profiling and cellular proof of concept |
| work_keys_str_mv | AT hudsonl novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT muij novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT vazquezs novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT carvalhod novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT williamse novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT jonesc novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT bullocka novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept AT hoelders novelquinazolinoneinhibitorsofalk2flipbetweenalternatebindingmodesstructureactivityrelationshipstructuralcharacterizationkinaseprofilingandcellularproofofconcept |