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

Pissot Soldermann, Carole and Simic, Oliver and Renatus, Martin and Erbel, Paulus and Melkko, Samu and Wartmann, Markus and Bigaud, Marc and Weiss, Andreas and Mcsheehy, Paul M.J. and Endres, Ralf and Fernandes Gomes Dos Santos, Paulo Antonio and Blank, Jutta and Schuffenhauer, Ansgar and Bold, Guido and Buschmann, Nicole and Zoller, Thomas and Altmann, Eva and Manley, Paul and Dix, Ina and Buchdunger, Elisabeth and Scesa, Julien and Quancard, Jean and Schlapbach, Achim and Bornancin, Frederic and Radimerski, Thomas and Regnier, Catherine (2020) Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing. Journal of medicinal chemistry. pp. 14576-14583.

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 in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.

Item Type: Article
Keywords: MALT1 inhibitor, allosteric
Date Deposited: 27 Jul 2021 00:45
Last Modified: 27 Jul 2021 00:45
URI: https://oak.novartis.com/id/eprint/43677

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