Identification of Rapaglutin E as an Isoform-Specific Inhibitor of Glucose Transporter 1
Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of hybrid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glucose transporter (GLUT), rapaglutin A (RgA), was previously identified. RgA is a pan-GLUT inhibitor of Class I isoforms GLUT1, GLUT3, and GLUT4. Herein, we report the discovery of rapaglutin E (RgE). Unlike RgA, RgE is highly specific for GLUT1. Further characterization revealed that RgE and RgA likely bound to distinct sites on GLUT1 despite their shared FKBP-binding domain, suggesting that the distinct effector domains of RgE and RgA play key roles in the recognition of GLUTs.
Authors
- Jun O. Liu (ORCID: https://orcid.org/0000-0003-3842-9841)
- Zhongnan Ma (ORCID: https://orcid.org/0000-0003-1457-0330)
- Cordelia Schiene‐Fischer
- Hanjing Peng
- Max Kotlyar (ORCID: https://orcid.org/0000-0002-1111-8667)
- Alka Rao (ORCID: https://orcid.org/0000-0002-5032-2169)
- Jingxin Wang (ORCID: https://orcid.org/0000-0002-9414-4093)
- Zufeng Guo (ORCID: https://orcid.org/0000-0002-4370-9445)
- Günter Fischer
Institutions
- Johns Hopkins University (US)
- Luther University (KR)
- Interface (United States) (US)
- Institute of Molecular Life Sciences (HU)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Martin Luther University Halle-Wittenberg (DE)
Publication Details
- Journal
- ACS Chemical Biology
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1021/acschembio.5c00152
- Citations
- 2
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Damon Runyon Cancer Research Foundation
- National Cancer Institute
- National Institute of General Medical Sciences