Kinase chemodiversity from the Arctic: the breitfussins
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...
Published in: | Journal of Medicinal Chemistry |
---|---|
Main Authors: | , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
ACS
2020
|
Subjects: | |
Online Access: | https://hdl.handle.net/1956/23715 https://doi.org/10.1021/acs.jmedchem.9b01006 |
id |
ftunivbergen:oai:bora.uib.no:1956/23715 |
---|---|
record_format |
openpolar |
spelling |
ftunivbergen:oai:bora.uib.no:1956/23715 2023-05-15T14:57:06+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 2020-02-12T14:40:53Z application/pdf https://hdl.handle.net/1956/23715 https://doi.org/10.1021/acs.jmedchem.9b01006 eng eng ACS Norges forskningsråd: 244264 Norges forskningsråd: 174885 urn:issn:1520-4804 urn:issn:0022-2623 https://hdl.handle.net/1956/23715 https://doi.org/10.1021/acs.jmedchem.9b01006 cristin:1746797 Journal of Medicinal Chemistry. 2019;62(22):10167-10181 Copyright 2019 American Chemical Society Journal of Medicinal Chemistry 10167-10181 62 22 Peer reviewed Journal article 2020 ftunivbergen https://doi.org/10.1021/acs.jmedchem.9b01006 2023-03-14T17:43:08Z 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. acceptedVersion Article in Journal/Newspaper Arctic University of Bergen: Bergen Open Research Archive (BORA-UiB) Arctic Journal of Medicinal Chemistry 62 22 10167 10181 |
institution |
Open Polar |
collection |
University of Bergen: Bergen Open Research Archive (BORA-UiB) |
op_collection_id |
ftunivbergen |
language |
English |
description |
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. acceptedVersion |
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 |
spellingShingle |
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 |
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 |
ACS |
publishDate |
2020 |
url |
https://hdl.handle.net/1956/23715 https://doi.org/10.1021/acs.jmedchem.9b01006 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Journal of Medicinal Chemistry 10167-10181 62 22 |
op_relation |
Norges forskningsråd: 244264 Norges forskningsråd: 174885 urn:issn:1520-4804 urn:issn:0022-2623 https://hdl.handle.net/1956/23715 https://doi.org/10.1021/acs.jmedchem.9b01006 cristin:1746797 Journal of Medicinal Chemistry. 2019;62(22):10167-10181 |
op_rights |
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 |
_version_ |
1766329198046085120 |