Development of High-Affinity Ligands for Human UBR2
∼ 20-40 nM and with 10-fold selectivity over UBR2's closest homologue, UBR1. High-resolution cocrystal structures (∼1.2 Å) of UBR2 in complexes with two high-affinity tripeptides revealed molecular mechanisms for their high-affinity binding. Importantly, a high-affinity UBR2 ligand effectively attenuated cancer-induced cachexia in a cellular model. Our findings demonstrate that the UBR boxes are ligandable and thus could spur interest in targeting this class of E3 ligases for developing novel therapeutic approaches for the treatment of cachexia and other illnesses.
Authors
- Tianchen Ren (ORCID: https://orcid.org/0009-0009-5241-4022)
- Abdelfattah Faouzi (ORCID: https://orcid.org/0000-0002-9059-4791)
- Yixuan Kuang (ORCID: https://orcid.org/0009-0004-3802-0418)
- Susan Taylor (ORCID: https://orcid.org/0000-0002-7702-6108)
- Jian Wu
- Nicole Thomas
- Shih-Ting Huang (ORCID: https://orcid.org/0000-0003-3862-564X)
- Dai-Hua Chen
- Yuan Chen
- Kersi Pestonjamasp
Institutions
- University of California San Diego (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-05-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02881
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute
- National Institute of General Medical Sciences
- U.S. Army Medical Research Acquisition Activity