Stabilizing Inactive Conformations of MALT1 as an Effective Approach to Inhibit Its Protease Activity

Abstract

The paracaspase MALT1 (mucosa associated lymphoid tissue lymphoma translocated gene 1) plays an important role in various immune pathways and is proposed as a therapeutic target for autoimmune disorders as well as different types of cancer, such as diffuse large B‐cell lymphoma (DLBCL). Different mechanisms are explored to inhibit the protease activity of MALT1 and two unrelated chemical scaffolds are discovered. Biophysical and structural studies reveal that both scaffolds stabilize the protease in an inactive conformation. While one ligand binds to the allosteric site at the interface between the caspase and the Ig3 domain, the other ligand binds to the active site using a so far undescribed mechanism. Iterative structure‐based drug discovery on one scaffold results in the identification of a potent, selective, and orally bioavailable MALT1 inhibitor.

Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing

“…Expression and purification of MALT1 Casp1‑Ig3 for crystallization and biophysical studies have been described. , MALT1(329–728) at 12 mg/mL, in 25 mM HEPES pH7.5, 50 mM NaCl, and 1 mM TCEP, was mixed with TC1 in 100% DMSO at a final concentration of 0.5 mM. TCEP (10 mM) and MgCl 2 (10 mM) were added to the protein before setup.…”

Anticancer Activity of Lesbicoumestan in Jurkat Cells via Inhibition of Oxidative Stress-Mediated Apoptosis and MALT1 Protease

“…To explore the possible binding mode of lesbicoumestan to MALT1, we obtained the crystal structure of MALT1 as a template (3UO8) [ 16 ] from the Protein Data Bank [ 17 , 18 ] and a docking study was conducted to rationalize the inhibitory activity of lesbicoumestan using Autodock4 [ 19 ]. For binding pocket estimation, we selected the pocket in which the origin ligand posed, which was previously reported as a known paracaspase domain of MALT1 [ 16 , 20 ]. By comparing lesbicoumestan to the reported MALT1 inhibitor β-lapachone, we found that both were structurally similar molecules and had a partially closed scaffold.…”