9MKC の概要
| エントリーDOI | 10.2210/pdb9mkc/pdb |
| 分子名称 | Mucosa-associated lymphoid tissue lymphoma translocation protein 1, CALCIUM ION, N-[(8R)-2-chloro-7-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]-N'-[5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]urea (3 entities in total) |
| 機能のキーワード | allosteric inhibitor, hydrolase |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 88729.74 |
| 構造登録者 | |
| 主引用文献 | Nie, Z.,Trzoss, M.,Placzek, A.T.,Trzoss, L.,Krilov, G.,Feng, S.,Lawrenz, M.,Ye, M.,Marshall, N.,Dingley, K.H.,Pelletier, R.D.,Lai, W.G.,Bell, J.A.,Tang, H.,Devine, P.,Liu, Z.,Skrdla, P.,Shimanovich, R.,Liu, M.,Wang, R.,Xu, X.,Abel, R.,Akinsanya, K.,Yin, W. Accelerated In Silico Discovery of SGR-1505 : A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies. J.Med.Chem., 2025 Cited by PubMed Abstract: MALT1 is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-κB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin's B-cell lymphomas. By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and a chemistry-aware compound enumeration workflow, extensive sets of design ideas were explored to quickly identify a novel hit series. Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, , with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms. PubMed: 41078320DOI: 10.1021/acs.jmedchem.5c01494 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.8 Å) |
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