Rapamycin-inspired macrocycles with new target specificity
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Abstract
Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles (named rapafucins) using optimized FKBP-binding domains. Screening of the rapafucin library in human cells led to the discovery of rapadocin, an inhibitor of nucleoside uptake. Rapadocin is a potent, isoform-specific and FKBP-dependent inhibitor of the equilibrative nucleoside transporter 1 and is efficacious in an animal model of kidney ischaemia reperfusion injury. Together, these results demonstrate that rapafucins are a new class of chemical probes and drug leads that can expand the repertoire of protein targets well beyond mTOR and calcineurin.
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Analogs of rapamycin and thalidomide can maintain binding to FKBP12 and cereblon respectively, but shift their neo-substrate binding profiles to confer new and distinct biological functions.
“Moreover, analogs of rapamycin and thalidomide can still maintain binding to FKBP12 and cereblon respectively, but shift their neo-substrate binding profiles to confer new and distinct biological functions 13,14.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [13]
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- Authors
- Guo, Z., Hong, S. Y., Wang, J., Rehan, S., Liu, W., Peng, H., Das, M., Li, W., Bhat, S., Peiffer, B., Ullman, B. R., Tse, C.-M., Tarmakova, Z., Schiene-Fischer, C., Fischer, G., Coe, I., Paavilainen, V. O., Sun, Z., & Liu, J. O.
- Affiliations
- Johns Hopkins University (US)
- Scripps Research Institute (US)
- University of Helsinki (FI)
- Nanjing University of Chinese Medicine (CN)
- United States Food and Drug Administration (US)
- Baltimore Museum of Art (US)
- Toronto Metropolitan University (CA)
- Martin Luther University Halle-Wittenberg (DE)
- Corresponding author
- Liu, Jun O.
- ORCID
- Venue
- Nature Chemistry
- Published
- 2018-12-10
- Volume
- 11
- Issue
- 3
- Pages
- 254-263
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC6435255
- OpenAlex
- W2902492842
- Cited by
- 120
- References
- 61
- Citations by year
- 2026: 7 · 2025: 29 · 2024: 19 · 2023: 10 · 2022: 13 · 2021: 16 · 2020: 16 · 2019: 10
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- National Institutes of Health (DP1OD006795)
- National Cancer Institute (DP1CA174428)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK089502)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Supramolecular Chemistry and Complexes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- rapamycin, FK506, macrocycles, ring-closing metathesis, equilibrative nucleoside transporter 1, hENT1, chemical probes, drug leads, mTOR, calcineurin
- MeSH terms
- Animals, Cell Line, Humans, Swine, Reperfusion Injury, Tacrolimus, Macrolides, Protective Agents, Sirolimus, Proteome, Tacrolimus Binding Proteins, Mice, Drug Discovery, Acute Kidney Injury, TOR Serine-Threonine Kinases, Human Umbilical Vein Endothelial Cells
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