9QFS

Structure of CHIP E3 ubiquitin ligase TPR domain in complex with compound 8.

This is a non-PDB format compatible entry.

Summary for 9QFS

• Entry DOI: 10.2210/pdb9qfs/pdb
• Descriptor: E3 ubiquitin-protein ligase CHIP, ~{N}-[(4~{R})-4-cyclohexyl-2,5-bis(oxidanylidene)imidazolidin-1-yl]-4,5,6,7-tetrakis(fluoranyl)-1~{H}-indole-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: e3 ubiquitin ligase, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 16110.19

Authors

Breed, J. (deposition date: 2025-03-12, release date: 2025-08-27)

Primary citation

Lucas, S.C.C.,Milbradt, A.G.,Breed, J.,De Genst, E.,Jackson, A.,Solovyeva, A.,Ackroyd, B.,Bauer, M.R.,Liu, J.,Longmire, D.,Petrovic, D.,Rivers, E.L.,Stubbs, C.,Winlow, P.,Bazzaz, S.,Dickson, P.,Gikunju, D.,Guie, M.A.,Guilinger, J.P.,Hupp, C.D.,Jetson, R.,Keefe, A.D.,Nugai, K.,Yeoman, J.T.S.,Zhang, Y.,Feng, X.,Yu, D.,Phillips, C.
Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP from a DNA-Encoded Library Screen.
Acs Med.Chem.Lett., 16:1445-1451, 2025

PubMed Abstract: STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound , which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.

PubMed: 40832528
DOI: 10.1021/acsmedchemlett.5c00361

Experimental method

X-RAY DIFFRACTION (1.329 Å)