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Kinase chemodiversity from the Arctic: the breitfussins
- Source :
- Journal of Medicinal Chemistry
- Publication Year :
- 2019
- Publisher :
- ACS, 2019.
-
Abstract
- 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.
- Subjects :
- Embryo, Nonmammalian
Indoles
kjemisk struktur
PIM1
Antineoplastic Agents
Triple Negative Breast Neoplasms
01 natural sciences
Mice
03 medical and health sciences
Adenosine Triphosphate
Proto-Oncogene Proteins c-pim-1
karbon
Cell Line, Tumor
Toxicity Tests
Drug Discovery
Animals
Humans
Protein Kinase Inhibitors
IC50
Zebrafish
Triple-negative breast cancer
030304 developmental biology
ADME
Biological Products
0303 health sciences
Binding Sites
Molecular Structure
VDP::Mathematics and natural science: 400::Chemistry: 440
Arctic Regions
Kinase
Chemistry
Mathematics and natural science: 400::Chemistry: 440 [VDP]
Total synthesis
In vitro
Hydrocarbons, Brominated
0104 chemical sciences
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
Hydrozoa
Biochemistry
Cell culture
VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440
peptider
Molecular Medicine
Female
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....f00ae26345ddae05df071a57cf3185cf