Kinase chemodiversity from the Arctic: the breitfussins
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles o...
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Main Authors: | , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
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American Chemical Society
2019
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Online Access: | https://hdl.handle.net/10037/17555 https://doi.org/10.1021/acs.jmedchem.9b01006 |
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ftunivtroemsoe:oai:munin.uit.no:10037/17555 2023-05-15T14:27:53+02:00 Kinase chemodiversity from the Arctic: the breitfussins Østnes Hansen, Kine Andersen, Jeanette hammer Bayer, Annette Pandey, Sunil Kumar Lorentzen, Marianne Jørgensen, Kåre Bredeli Sydnes, Magne Olav Guttormsen, Yngve Baumann, Matthias Koch, Uwe Klebl, Bert Eickhoff, Jan Haug, Bengt Erik Isaksson, Johan Hansen, Espen 2019-10-24 https://hdl.handle.net/10037/17555 https://doi.org/10.1021/acs.jmedchem.9b01006 eng eng American Chemical Society Journal of Medicinal Chemistry Norges forskningsråd: 244264 Norges forskningsråd: 174885 info:eu-repo/grantAgreement/RCN/SFI/174885/Norway/MabCent - Centre on Marine Bioactives and Drug Discovery// info:eu-repo/grantAgreement/RCN/BIOTEK2021/244264/Norway/Potent and selective protein kinase inhibitors from the sea// Østnes Hansen KØH, Andersen Jh, Bayer A, Pandey SK, Lorentzen M, Jørgensen KB, Sydnes MO, Guttormsen Y, Baumann M, Koch, Klebl B, Eickhoff J, Haug BE, Isaksson J, Hansen E. Kinase chemodiversity from the Arctic: the breitfussins. Journal of Medicinal Chemistry. 2019;62(22):10167-10181 FRIDAID 1746797 doi:10.1021/acs.jmedchem.9b01006 0022-2623 1520-4804 https://hdl.handle.net/10037/17555 openAccess Copyright © 2019 American Chemical Society VDP::Mathematics and natural science: 400::Chemistry: 440 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440 Journal article Tidsskriftartikkel Peer reviewed acceptedVersion 2019 ftunivtroemsoe https://doi.org/10.1021/acs.jmedchem.9b01006 2021-06-25T17:57:15Z This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.9b01006. In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C–H (3 – 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors. Article in Journal/Newspaper Arctic Arctic University of Tromsø: Munin Open Research Archive Arctic Journal of Medicinal Chemistry 62 22 10167 10181 |
institution |
Open Polar |
collection |
University of Tromsø: Munin Open Research Archive |
op_collection_id |
ftunivtroemsoe |
language |
English |
topic |
VDP::Mathematics and natural science: 400::Chemistry: 440 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440 |
spellingShingle |
VDP::Mathematics and natural science: 400::Chemistry: 440 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440 Østnes Hansen, Kine Andersen, Jeanette hammer Bayer, Annette Pandey, Sunil Kumar Lorentzen, Marianne Jørgensen, Kåre Bredeli Sydnes, Magne Olav Guttormsen, Yngve Baumann, Matthias Koch, Uwe Klebl, Bert Eickhoff, Jan Haug, Bengt Erik Isaksson, Johan Hansen, Espen Kinase chemodiversity from the Arctic: the breitfussins |
topic_facet |
VDP::Mathematics and natural science: 400::Chemistry: 440 VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440 |
description |
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.9b01006. In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C–H (3 – 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors. |
format |
Article in Journal/Newspaper |
author |
Østnes Hansen, Kine Andersen, Jeanette hammer Bayer, Annette Pandey, Sunil Kumar Lorentzen, Marianne Jørgensen, Kåre Bredeli Sydnes, Magne Olav Guttormsen, Yngve Baumann, Matthias Koch, Uwe Klebl, Bert Eickhoff, Jan Haug, Bengt Erik Isaksson, Johan Hansen, Espen |
author_facet |
Østnes Hansen, Kine Andersen, Jeanette hammer Bayer, Annette Pandey, Sunil Kumar Lorentzen, Marianne Jørgensen, Kåre Bredeli Sydnes, Magne Olav Guttormsen, Yngve Baumann, Matthias Koch, Uwe Klebl, Bert Eickhoff, Jan Haug, Bengt Erik Isaksson, Johan Hansen, Espen |
author_sort |
Østnes Hansen, Kine |
title |
Kinase chemodiversity from the Arctic: the breitfussins |
title_short |
Kinase chemodiversity from the Arctic: the breitfussins |
title_full |
Kinase chemodiversity from the Arctic: the breitfussins |
title_fullStr |
Kinase chemodiversity from the Arctic: the breitfussins |
title_full_unstemmed |
Kinase chemodiversity from the Arctic: the breitfussins |
title_sort |
kinase chemodiversity from the arctic: the breitfussins |
publisher |
American Chemical Society |
publishDate |
2019 |
url |
https://hdl.handle.net/10037/17555 https://doi.org/10.1021/acs.jmedchem.9b01006 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic Arctic |
genre_facet |
Arctic Arctic |
op_relation |
Journal of Medicinal Chemistry Norges forskningsråd: 244264 Norges forskningsråd: 174885 info:eu-repo/grantAgreement/RCN/SFI/174885/Norway/MabCent - Centre on Marine Bioactives and Drug Discovery// info:eu-repo/grantAgreement/RCN/BIOTEK2021/244264/Norway/Potent and selective protein kinase inhibitors from the sea// Østnes Hansen KØH, Andersen Jh, Bayer A, Pandey SK, Lorentzen M, Jørgensen KB, Sydnes MO, Guttormsen Y, Baumann M, Koch, Klebl B, Eickhoff J, Haug BE, Isaksson J, Hansen E. Kinase chemodiversity from the Arctic: the breitfussins. Journal of Medicinal Chemistry. 2019;62(22):10167-10181 FRIDAID 1746797 doi:10.1021/acs.jmedchem.9b01006 0022-2623 1520-4804 https://hdl.handle.net/10037/17555 |
op_rights |
openAccess Copyright © 2019 American Chemical Society |
op_doi |
https://doi.org/10.1021/acs.jmedchem.9b01006 |
container_title |
Journal of Medicinal Chemistry |
container_volume |
62 |
container_issue |
22 |
container_start_page |
10167 |
op_container_end_page |
10181 |
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1766301954272657408 |