8QTG
Crystal structure of CBL-b in complex with an allosteric inhibitor (compound 9)
Summary for 8QTG
| Entry DOI | 10.2210/pdb8qtg/pdb |
| Descriptor | E3 ubiquitin-protein ligase CBL-B, 3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1~{H}-pyridin-2-one, ZINC ION, ... (5 entities in total) |
| Functional Keywords | e3 ubiquitin ligase, allosteric inhibitor, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 46351.71 |
| Authors | Schimpl, M. (deposition date: 2023-10-12, release date: 2024-01-10, Last modification date: 2024-02-07) |
| Primary citation | Mfuh, A.M.,Boerth, J.A.,Bommakanti, G.,Chan, C.,Chinn, A.J.,Code, E.,Fricke, P.J.,Giblin, K.A.,Gohlke, A.,Hansel, C.,Hariparsad, N.,Hughes, S.J.,Jin, M.,Kantae, V.,Kavanagh, S.L.,Lamb, M.L.,Lane, J.,Moore, R.,Puri, T.,Quinn, T.R.,Reddy, I.,Robb, G.R.,Robbins, K.J.,Gancedo Rodrigo, M.,Schimpl, M.,Singh, B.,Singh, M.,Tang, H.,Thomson, C.,Walsh, J.J.,Ware, J.,Watson, I.D.G.,Ye, M.W.,Wrigley, G.L.,Zhang, A.X.,Zhang, Y.,Grimster, N.P. Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors. J.Med.Chem., 67:1500-1512, 2024 Cited by PubMed Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound . This compound binds to Cbl-b with an IC value of 30 nM and induces IL-2 production in T-cells with an EC value of 230 nM. Compound also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis. PubMed: 38227216DOI: 10.1021/acs.jmedchem.3c02083 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.419 Å) |
Structure validation
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