Summary for 8VW4
| Entry DOI | 10.2210/pdb8vw4/pdb |
| Descriptor | E3 ubiquitin-protein ligase CBL-B, MAGNESIUM ION, (7-methoxy-2-{2-[(1S,3S,4S)-3-(3-methoxy-2-methyl-5-nitrophenyl)-1-methyl-5-oxo-1,5-dihydroimidazo[1,5-a]pyridin-2(3H)-yl]-2-oxoethoxy}quinolin-8-yl)acetic acid, ... (6 entities in total) |
| Functional Keywords | ubiquitin ligase, e3, inhibitor, small molecule, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 73991.24 |
| Authors | |
| Primary citation | Liang, J.,Lambrecht, M.J.,Arenzana, T.L.,Aubert-Nicol, S.,Bao, L.,Broccatelli, F.,Cai, J.,Eidenschenk, C.,Everett, C.,Garner, T.,Gruber, F.,Haghshenas, P.,Huestis, M.P.,Hsu, P.L.,Kou, P.,Jakalian, A.,Larouche-Gauthier, R.,Leclerc, J.P.,Leung, D.H.,Martin, A.,Murray, J.,Prangley, M.,Rutz, S.,Kakiuchi-Kiyota, S.,Satz, A.L.,Skelton, N.J.,Steffek, M.,Stoffler, D.,Sudhamsu, J.,Tan, S.,Wang, J.,Wang, S.,Wang, Q.,Wendorff, T.J.,Wichert, M.,Yadav, A.,Yu, C.,Wang, X. Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding. Acs Med.Chem.Lett., 15:864-872, 2024 Cited by PubMed Abstract: We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound as a hit for which the -isomer () was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound , which demonstrated measurable cell activity, albeit only at high concentrations. PubMed: 38894924DOI: 10.1021/acsmedchemlett.4c00068 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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