Targeted Degradation of SLC Transporters Reveals Amenability of Multi-Pass Transmembrane Proteins to Ligand-Induced Proteolysis
Open accessAbstract
With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Engineering endogenous alleles via the degradation tag (dTAG) technology enabled chemical control of abundance of the transporter protein, SLC38A2. Moreover, we report the design of d9A-2, a chimeric compound engaging several members of the SLC9 family and leading to their degradation. d9A-2 impairs cellular pH homeostasis and promotes cell death in a range of cancer cell lines. These findings open the era of SLC-targeting chimeric degraders and demonstrate potential access of multi-pass transmembrane proteins of different subcellular localizations to the chemically exploitable degradation machinery.
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Bensimon et al. developed d9A-2, a pomalidomide-based PROTAC that degraded SLC9A1 and other SLC9 family members, leading to impaired pH homeostasis and cytotoxicity in multiple cancer cell lines via UPS-dependent TPD.
“Furthermore, they developed d9A-2, a pomalidomide-based PROTAC that degraded SLC family 9 member A1 (SLC9A1) — and, to a lesser extent, other SLC9 family members — leading to impaired pH homeostasis and cytotoxicity in multiple cancer cell lines, via a mechanism consistent with UPS-dependent TPD52.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [52]
Bensimon et al. showed that multi-transmembrane proteins from the SLC transporter family could be degraded using dTAG technology.
“Bensimon et al.52 challenged this view by showing that multi-transmembrane proteins from the solute carrier (SLC) transporter family could be degraded using the dTAG technology53.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [52]
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- Authors
- Bensimon, A., Pizzagalli, M. D., Kartnig, F., Dvorak, V., Essletzbichler, P., Winter, G. E., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 27
- Issue
- 6
- Pages
- 728-739.e9
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC7303955
- OpenAlex
- W3020980340
- Cited by
- 102
- References
- 61
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 17 · 2023: 14 · 2022: 14 · 2021: 18 · 2020: 15
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Vienna Science and Technology Fund
- Bayer
- Österreichischen Akademie der Wissenschaften
- Novartis
- Austrian Science Fund
- Sanofi
- Vifor Pharma
- Innovative Medicines Initiative
- European Research Council (695214)
- Boehringer Ingelheim
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- solute carrier transporters, SLC38A2, cancer cell death, protein degradation
- MeSH terms
- Protein Domains, Cell Line, Female, Humans, Hydrogen-Ion Concentration, Ligands, Male, Membrane Transport Proteins, Proteolysis
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