8VW5

Crystal structure of Cbl-b TKB bound to compound 2

これはPDB形式変換不可エントリーです。

8VW5 の概要

• エントリーDOI: 10.2210/pdb8vw5/pdb
• 関連するPDBエントリー: 8VW4
• 分子名称: E3 ubiquitin-protein ligase CBL-B, MAGNESIUM ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: ubiquitin ligase, e3, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73889.89

構造登録者

Yu, C.,Murray, J.,Hsu, P.L. (登録日: 2024-01-31, 公開日: 2024-07-03)

主引用文献

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

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: 38894924
DOI: 10.1021/acsmedchemlett.4c00068

実験手法

X-RAY DIFFRACTION (1.76 Å)