Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDBDonate
RCSB PDBPDBeBMRBAdv. SearchSearch help

8QNH

Crystal structure of the E3 ubiquitin ligase Cbl-b with an allosteric inhibitor (WO2020264398 Ex23)

Summary for 8QNH
Entry DOI10.2210/pdb8qnh/pdb
DescriptorE3 ubiquitin-protein ligase CBL-B, 2-{3-[(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one, ZINC ION, ... (5 entities in total)
Functional Keywordse3 ubiquitin ligase, allosteric inhibition, structure based drug design, ligase
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight46500.94
Authors
Schimpl, M. (deposition date: 2023-09-26, release date: 2023-11-22, Last modification date: 2024-01-03)
Primary citationBoerth, J.A.,Chinn, A.J.,Schimpl, M.,Bommakanti, G.,Chan, C.,Code, E.L.,Giblin, K.A.,Gohlke, A.,Hansel, C.S.,Jin, M.,Kavanagh, S.L.,Lamb, M.L.,Lane, J.S.,Larner, C.J.B.,Mfuh, A.M.,Moore, R.K.,Puri, T.,Quinn, T.R.,Ye, M.,Robbins, K.J.,Gancedo-Rodrigo, M.,Tang, H.,Walsh, J.,Ware, J.,Wrigley, G.L.,Reddy, I.K.,Zhang, Y.,Grimster, N.P.
Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.
Acs Med.Chem.Lett., 14:1848-1856, 2023
Cited by
PubMed Abstract: Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.
PubMed: 38116444
DOI: 10.1021/acsmedchemlett.3c00439
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.001 Å)
Structure validation

238895

건을2025-07-16부터공개중

PDB statisticsPDBj update infoContact PDBjnumon