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

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posted on 2020-11-30, 14:34 authored by Carole Pissot Soldermann, Oliver Simic, Martin Renatus, Paulus Erbel, Samu Melkko, Markus Wartmann, Marc Bigaud, Andreas Weiss, Paul McSheehy, Ralf Endres, Paulo Santos, Jutta Blank, Ansgar Schuffenhauer, Guido Bold, Nicole Buschmann, Thomas Zoller, Eva Altmann, Paul W. Manley, Ina Dix, Elisabeth Buchdunger, Julien Scesa, Jean Quancard, Achim Schlapbach, Frédéric Bornancin, Thomas Radimerski, Catherine H. Régnier
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 in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.