10ZF

Structure of c-Cbl bound to compound 33

This is a non-PDB format compatible entry.

Summary for 10ZF

• Entry DOI: 10.2210/pdb10zf/pdb
• Descriptor: Glutathione S-transferase class-mu 26 kDa isozyme,E3 ubiquitin-protein ligase CBL, 2-{3-[(1r,3r)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(1-methylcyclobutyl)amino]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one, ZINC ION, ... (5 entities in total)
• Functional Keywords: ubiquitin ligase, e3, inhibitor, ligase
• Biological source: Schistosoma japonicum (Blood fluke); More
• Total number of polymer chains: 1
• Total formula weight: 73482.52

Authors

Murray, J.,Yu, C.,Hsu, P.L. (deposition date: 2026-02-12, release date: 2026-07-01)

Primary citation

Liang, J.,Lambrecht, M.J.,Huestis, M.P.,Zhu, B.,Barton, L.M.,Castanedo, G.M.,Ung, P.M.,Larouche-Gauthier, R.,Jakalian, A.,Leclerc, J.P.,Yadav, A.,Haghshenas, P.,Aubert-Nicol, S.,Ismaili, H.,Zhao, L.,Leblanc, M.,de Almeida, H.,Wang, Q.,Garner, T.,Tan, S.,Prangley, M.S.,Pang, J.,Murray, J.M.,Yu, C.,Hsu, P.L.,Rutz, S.,Ishizuka, I.,Huang, H.,Gao, C.,Chen, M.,Mutter-Rottmayer, L.,Kakiuchi-Kiyota, S.,Leung, D.H.,Kou, P.,Bao, L.,Wang, X.
Optimization Leading to a Potent and Selective Cbl‐b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy.
Acs Med.Chem.Lett., 17:1258-1265, 2026

PubMed Abstract: In the preceding work in this issue (10.1021/acsmedchemlett.6c00103), we described our initial structure-activity relationship (SAR) optimization that led to a pan-Cbl inhibitor () that demonstrated efficacy in a mouse CT26 syngeneic model. Unfortunately, attempts to improve TGI with higher doses of resulted in poor tolerability which we attributed to a lack of selectivity between Cbl-b and c-Cbl (∼2× by surface plasmon resonance (SPR)). Herein, we report our continued efforts that led to a breakthrough in achieving Cbl-b selectivity (up to 37×). The lead compound demonstrated 14× selectivity against c-Cbl by SPR, was potent in a PBMC cell assay, and showed good oral exposure in mice. When tested in a CT26 model, displayed improved tumor growth inhibition compared to our previously reported pan-Cbl inhibitor (TGI 145% vs 82%). More importantly, was better tolerated than , supporting our hypothesis that a selective Cbl-b inhibitor could be advantageous relative to a pan-Cbl inhibitor.

PubMed: 42305193
DOI: 10.1021/acsmedchemlett.6c00104

Experimental method

X-RAY DIFFRACTION (2.39 Å)