Turner, LD, Summers, AJ, Johnson, LO et al. (2 more authors) (2017) Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design. ACS Medicinal Chemistry Letters, 8 (12). pp. 1264-1268. ISSN 1948-5875
Abstract
Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives. Biological evaluation revealed that these indazole-containing fragments inhibited FGFR1–3 in the range of 0.8–90 μM with excellent ligand efficiencies of 0.30–0.48. Some compounds exhibited moderate selectivity toward individual FGFRs, indicating that further optimization using SBDD may lead to potent and selective inhibitors of the FGFR family.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017, American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright (c) American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see: https://doi.org/10.1021/acsmedchemlett.7b00349 |
Keywords: | de novo; FGFR; fragment; indazole; SBDD |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Jan 2018 16:52 |
Last Modified: | 11 Nov 2018 01:39 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acsmedchemlett.7b00349 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125729 |