Targeted degradation of PCNA outperforms stoichiometric inhibition to result in programed cell death
Open accessPublished version of a preprint
Abstract
Biodegraders are targeted protein degradation constructs composed of mini-proteins/peptides linked to E3 ligase receptors. We gained deeper insights into their utility by studying Con1-SPOP, a biodegrader against proliferating cell nuclear antigen (PCNA), an oncology target. Con1-SPOP proved pharmacologically superior to its stoichiometric (non-degrading) inhibitor equivalent (Con1-SPOPmut) as it had more potent anti-proliferative effects and uniquely induced DNA damage, cell apoptosis, and necrosis. Proteomics showed that PCNA degradation gave impaired mitotic division and mitochondria dysfunction, effects not seen with the stoichiometric inhibitor. We further showed that doxycycline-induced Con1-SPOP achieved complete tumor growth inhibition in vivo. Intracellular delivery of mRNA encoding Con1-SPOP via lipid nanoparticles (LNPs) depleted endogenous PCNA within hours of application with nanomolar potency. Our results demonstrate the utility of biodegraders as biological tools and highlight target degradation as a more efficacious approach versus stoichiometric inhibition. Once in vivo delivery is optimized, biodegraders may be leveraged as an exciting therapeutic modality.
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- Authors
- Chang, S. C., Gopal, P., Lim, S., Wei, X., Chandramohan, A., Mangadu, R., Smith, J., Ng, S., Gindy, M., Phan, U., Henry, B., & Partridge, A. W.
- Affiliations
- MSD (Singapore) (SG)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Partridge, Anthony William
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 29
- Issue
- 11
- Pages
- 1601-1615.e7
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W4307905483
- Cited by
- 31
- References
- 13
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 9 · 2023: 7
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell chemical biology (publishedVersion)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- targeted protein degradation, PCNA, SPOP, E3 ubiquitin ligase, DNA damage, apoptosis, necrosis, mitotic division, mitochondrial dysfunction, tumor growth inhibition, mRNA delivery, lipid nanoparticles, doxycycline induction, antiproliferative activity
- MeSH terms
- Liposomes, Apoptosis, Proliferating Cell Nuclear Antigen, Ubiquitin-Protein Ligases, Nanoparticles
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