Turner, LD, Trinh, CH orcid.org/0000-0002-5087-5011, Hubball, RA et al. (5 more authors) (2022) From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor. Journal of Medicinal Chemistry, 65 (2). pp. 1481-1504. ISSN 0022-2623
Abstract
Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. Published by American Chemical Society. Available under licence Creative Commons Attribution (v4). |
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) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Plant Cell & Cellular Biology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Synthetic Biology (Leed) |
Funding Information: | Funder Grant number Cancer Research UK C6228/A12512 Yorkshire Cancer Research L376PA |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Nov 2021 15:19 |
Last Modified: | 18 Jul 2022 16:16 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.jmedchem.1c01163 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:179716 |