9MKD

Crystal structure of MALT1 in complex with an allosteric inhibitor

これはPDB形式変換不可エントリーです。

9MKD の概要

• エントリーDOI: 10.2210/pdb9mkd/pdb
• 分子名称: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, CALCIUM ION, TRIETHYLENE GLYCOL, ... (5 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: 89024.17

構造登録者

Bell, J.A. (登録日: 2024-12-17, 公開日: 2025-10-29, 最終更新日: 2025-12-10)

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.,Bhat, S.,Bos, P.H.,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., 68:23977-23992, 2025

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: 41078320
DOI: 10.1021/acs.jmedchem.5c01494

実験手法

X-RAY DIFFRACTION (2.45 Å)