Rewiring the SUMO–Ubiquitin System for Next-Generation Therapies
- Jacqueline Kandsberger
- 2 days ago
- 2 min read
In their recent review (published in Trends in Pharmacological Sciences) Gina Gotthardt, PROXIDRUGS researcher Jan Keiten-Schmitz, and PROXIDRUG PI Stefan Müller discuss how SUMO-signaling and SUMO-targeted ubiquitin ligases (StUbLs) can be exploited to inactivate disease-associated proteins. The review explores the new therapeutic possibilities that this opens within the field of drug discovery utilizing the ubiquitin-proteasome system.
Established cancer treatments are harnessing the SUMO–StUbL system to degrade or inactivate the oncoproteins PML-RARα and estrogen receptor alpha (ERα), which are associated with acute promyelocytic leukemia and breast cancer, respectively. StUbL-based PROTACs and SUMO-targeting chimeras (SUTACs), hold promise to selectively inactivate oncogenic transcription factors to rewire cancer-associated transcriptional programs. Proximity-based drugs which induce SUMOylation and SUMO-primed ubiquitylation through target specific ligase recruitment could act as dual-hit compounds that combine transcriptional repression with targeted degradation of oncoproteins.
In neurodegeneration, redirecting SUMOylation and StUbL activity by recruiting aggregation-prone proteins like TDP-43 to PML nuclear bodies offers a potential strategy to reprogram proteostasis networks to limiting toxic aggregates in ALS, Alzheimer’s disease and related disorders.
While many new insights on StUbL-based therapeutics and SUMO–StUbL signaling have emerged, more work remains to be done regarding the definition of optimal SUMO–StUbL signatures and the identification of specific binders of SUMO-ligases, StUbLs and target proteins as prerequisites for the development of SUTACs and StUbL-based PROTACs.
Gotthardt G, Keiten-Schmitz J, Müller S. Reprogramming SUMO-primed ubiquitylation: opportunities in oncology and neurology. Trends Pharmacol Sci. 2025 Oct 1:S0165-6147(25)00205-6. https://doi.org/10.1016/j.tips.2025.09.002
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Recent associated publication from the Müller Lab:
K. Wagner, J. Keiten-Schmitz, et al. Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks Nat. Chem. Biol., 21 (2025), pp. 1408-1419 https://doi.org/10.1038/s41589-025-01886-4
Figure 3. SUMO-targeting chimeras (SUTACs) and promyelocytic leukemia protein (PML) recruiters as therapeutic modalities.