7AK1

Human MALT1(329-729) in complex with a chromane urea containing inhibitor

7AK1 の概要

• エントリーDOI: 10.2210/pdb7ak1/pdb
• 分子名称: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, 1-(3-chloranyl-4-methoxy-phenyl)-3-[7-[(3~{S})-3-(methoxymethyl)morpholin-4-yl]-2-methyl-pyrazolo[1,5-a]pyrimidin-6-yl]urea, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, allosteric inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46164.60

構造登録者

Renatus, M. (登録日: 2020-09-29, 公開日: 2020-12-09, 最終更新日: 2024-01-31)

主引用文献

Pissot Soldermann, C.,Simic, O.,Renatus, M.,Erbel, P.,Melkko, S.,Wartmann, M.,Bigaud, M.,Weiss, A.,McSheehy, P.,Endres, R.,Santos, P.,Blank, J.,Schuffenhauer, A.,Bold, G.,Buschmann, N.,Zoller, T.,Altmann, E.,Manley, P.W.,Dix, I.,Buchdunger, E.,Scesa, J.,Quancard, J.,Schlapbach, A.,Bornancin, F.,Radimerski, T.,Regnier, C.H.
Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing.
J.Med.Chem., 63:14576-14593, 2020

PubMed Abstract: MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both and profiling of MLT-231 support further optimization of this tool compound toward preclinical characterization.

PubMed: 33252239
DOI: 10.1021/acs.jmedchem.0c01245

実験手法

X-RAY DIFFRACTION (2.507 Å)