# Targeting Glucose Transporters Using Rapafucins

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $335,688

## Abstract

A major challenge in drug discovery is to identify small molecule inhibitors for the
challenging targets including protein-protein interactions and multi-pass
transmembrane proteins. Nature has evolved an ingenious solution to this problem
as exemplified by the immunophilin ligand family of macrocyclic natural products,
including rapamycin and FK506. Aside from their own larger sizes that enable
more extensive interactions with proteins, these natural products also recruit the
FKBP-family of chaperones to form much larger dimeric complexes before
associating with their respective targets, mTOR and calcineurin. Inspired by this
unique mode of action, we generated a 45,000-compound library of rapamycin-like
macrocycles, named rapafucins, by fusing the FKBP-binding domain of rapamycin
with a combinatorial tetrapeptide library. Screening of this library has led to the
discovery of multiple members of the solute carrier (SLC) transporter superfamily,
including members of the glucose transporter (GLUT) family. Two distinct inhibitors
of GLUT were identified, rapaglutin A (RgA) and rapaglutin E (RgE). Whereas RgE
is highly specific for GLUT1, RgA seems to inhibit multiple GLUT isoforms. RgA
has been shown to be efficacious in a xenograft model of breast cancer while RgE
was found to inhibit intracellular T cell receptor signaling by blocking the DNA-
binding activity of NFAT. We will further characterize the antitumor activity of RgA
by systematically assessing its effect on cellular metabolomic profiles and the
AMPK-mTOR signaling pathway. In preliminary studies, we have found that RgA
and phenformin have synergy in inhibiting triple negative breast cancer cells
(TNBC). We will further delineate the mechanism of synergy and the effect of the
RgA-phenfomin combination for inhibiting TNBC tumor growth in vivo. That RgE
inhibited calcium stimulated DNA-binding activity of NFAT suggests a potential role
of GLUT1 in regulating intracellular T cell receptor signaling. We will elucidate the
mechanism underlying the immunsuppressive activity of RgE and investigate the
potential of RgE as an immunosuppressant in vivo. Lastly, using a newly
developed microarray platform, we will screen rapafucin libraries against each of
the 14 isoforms of GLUTs in search of specific inhibitors of different isoforms of
GLUT, which can become new chemical tools for studying the biology of GLUT.

## Key facts

- **NIH application ID:** 10124420
- **Project number:** 5R01GM137319-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jun O. Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,688
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124420

## Citation

> US National Institutes of Health, RePORTER application 10124420, Targeting Glucose Transporters Using Rapafucins (5R01GM137319-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124420. Licensed CC0.

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