Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing PMID: 33252239

Target-related Cytokines

2026-09-23

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

J Med Chem. 2020 Dec 10;63(23):14576-14593. doi: 10.1021/acs.jmedchem.0c01245.

Carole Pissot Soldermann ¹ , Oliver Simic ¹ , Martin Renatus ¹ , Paulus Erbel ¹ , Samu Melkko ¹ , Markus Wartmann ¹ , Marc Bigaud ¹ , Andreas Weiss ¹ , Paul McSheehy ² , Ralf Endres , Paulo Santos , Jutta Blank ¹ , Ansgar Schuffenhauer ¹ , Guido Bold ¹ , Nicole Buschmann ¹ , Thomas Zoller ¹ , Eva Altmann ¹ , Paul W Manley ¹ , Ina Dix ¹ , Elisabeth Buchdunger ¹ , Julien Scesa ¹ , Jean Quancard ¹ , Achim Schlapbach ¹ , Frédéric Bornancin ¹ , Thomas Radimerski ² , Catherine H Régnier ¹

Affiliations

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.