7AK0

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

Summary for 7AK0

• Entry DOI: 10.2210/pdb7ak0/pdb
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, 1-[4-[4-(aminomethyl)pyrazol-1-yl]-3-chloranyl-phenyl]-3-[(3~{R})-6-bromanyl-3,4-dihydro-2~{H}-chromen-3-yl]urea (3 entities in total)
• Functional Keywords: inhibitor, complex, allosteric inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 92312.27

Authors

Renatus, M. (deposition date: 2020-09-29, release date: 2020-12-09, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.316 Å)